Succinoylamino hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors

ABSTRACT

Succinoylamino hydroxyethylamino sulfonyl urea derivatives of the formula:  
                 
 
wherein R 1 -R 6 , R 7 , R 7′ , R 8 , R 30 -R 34 , X′, Y, Y′, t, x, and n are as defined herein, are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to retroviral protease inhibitors and,more particularly, relates to novel compounds and a composition andmethod for inhibiting retroviral proteases. This invention, inparticular, relates to derivatives of sulfamic acid-containinghydroxyethylamine protease inhibitor compounds, a composition and methodfor inhibiting retroviral proteases such as human immunodeficiency virus(HIV) protease and for treating a retroviral infection, e.g., an HIVinfection. The subject invention also relates to processes for makingsuch compounds as well as to intermediates useful in such processes.

2. Related Art

During the replication cycle of retroviruses, gag and gag-pol geneproducts are translated as proteins. These proteins are subsequentlyprocessed by a virally encoded protease (or proteinase) to yield viralenzymes and structural proteins of the virus core. Most commonly, thegag precursor proteins are processed into the core proteins and the polprecursor proteins are processed into the viral enzymes, e.g., reversetranscriptase and retroviral protease. It has been shown that correctprocessing of the precursor proteins by the retroviral protease isnecessary for assembly of infectious virons. For example, it has beenshown that frameshift mutations in the protease region of the pol geneof HIV prevents processing of the gag precursor protein. It has alsobeen shown through site-directed mutagenesis of an aspartic acid residuein the HIV protease that processing of the gag precursor protein isprevented. Thus, attempts have been made to inhibit viral replication byinhibiting the action of retroviral proteases.

Retroviral protease inhibition may involve a transition-state mimeticwhereby the retroviral protease is exposed to a mimetic compound whichbinds to the enzyme in competition with the gag and gag-pol proteins tothereby inhibit replication of structural proteins and, moreimportantly, the retroviral protease itself. In this manner, retroviralreplication proteases can be effectively inhibited.

Several classes of compounds have been proposed, particularly forinhibition of proteases, such as for inhibition of HIV protease. Suchcompounds include hydroxyethylamine isosteres and reduced amideisosteres. See, for example, EP O 346 847; EP O 342,541; Roberts et al,“Rational Design of Peptide-Based Proteinase Inhibitors,” Science, 248,358 (1990); and Erickson et al, “Design Activity, and 2.8 Å CrystalStructure of a C₂ Symmetric Inhibitor Complexed to HIV-1 Protease,”Science, 249, 527 (1990).

Several classes of compounds are known to be useful as inhibitors of theproteolytic enzyme renin. See, for example, U.S. Pat. No. 4,599,198;U.K. 2,184,730; G.B. 2,209,752; EP O 264 795; G.B. 2,200,115 and U.S.SIR H725. Of these, G.B. 2,200,115, GB 2,209,752, EP O 264,795, U.S. SIRH725 and U.S. Pat. No. 4,599,198 disclose urea-containinghydroxyethylamine renin inhibitors. G.B. 2,200,115 also disclosessulfamic acid-containing hydroxyethylamine renin inhibitors, and EP 0264795 discloses certain sulfamic acid-containing hydroxyethylamine renininhibitors. However, it is known that, although renin and HIV proteasesare both classified as aspartyl proteases, compounds which are effectiverenin inhibitors generally cannot be predicted to be effective HIVprotease inhibitors.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is directed to virus inhibiting compounds andcompositions. More particularly, the present invention is directed toretroviral protease inhibiting compounds and compositions, to a methodof inhibiting retroviral proteases, to processes for preparing thecompounds and to intermediates useful in such processes. The subjectcompounds are characterized as derivatives of succinoylaminohydroxyethylamino sulfonyl urea inhibitor compounds.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a retroviralprotease inhibiting compound of the formula:

or a pharmaceutically acceptable salt, prodrug or ester thereof wherein:

-   R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,    —CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),    —C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl and    cycloalkyl radicals, and amino acid side chains selected from    asparagine, S-methyl cysteine methionine and the sulfoxide (SO) and    sulfone (SO₂) derivatives thereof, isoleucine, allo-isoleucine,    alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine,    norleucine, glutamine, threonine, glycine, allo-threonine, serine,    O-alkyl serine, aspartic acid, beta-cyanoalanine and valine side    chains;-   R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl    radicals, which radicals are optionally substituted with a group    selected from alkyl and halogen radials, —NO₂, —CN, —CF₃, —OR⁹ and    —SR⁹, wherein R⁹ represents hydrogen and alkyl radicals;-   R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,    alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,    heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl,    aminoalkyl and mono- and disubstituted aminoalkyl radicals, wherein    said substituents are selected from alkyl, aryl, aralkyl,    cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,    heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case    of a disubstituted aminoalkyl radical, said substituents along with    the nitrogen atom to which they are attached, form a    heterocycloalkyl or a heteroaryl radical, and thioalkyl,    alkylthioalkyl and arylthioalkyl radicals and the sulfone and    sulfoxide derivatives thereof;-   R⁴ represents hydrogen and radicals as defined by R³;-   R⁶ represents hydrogen and alkyl radicals;-   R⁷ and R^(7′) independently represent hydrogen and radicals as    defined for R³, amino acid side chains selected from the group    consisting of valine, isoleucine, glycine, alanine, allo-isoleucine,    asparagine, leucine, glutamine, and t-butylglycine; radicals    represented by the formulas —C(O)R¹⁶, —CO₂R¹⁶, —SO₂R¹⁶, —SR¹⁶,    —CONR¹⁶R¹⁷, —CF₃ and —NR¹⁶R¹⁷; or R⁷ and R^(7′) together with the    carbon atom to which they are attached form a cycloalkyl or    heterocycloalkyl radical;-   R⁸ represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl,    aralkyl, heterocycloalkyl and heteroaryl radicals and radicals    represented by the formulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶, SR¹⁶,    CONR¹⁶R¹⁷, CF₃ and NR¹⁶R¹⁷;-   wherein R¹⁶ and R¹⁷ independently represent hydrogen and radicals as    defined for R³, or R¹⁶ and R¹⁷ together with a nitrogen to which    they are attached in the formula NR¹⁶R¹⁷ represent heterocycloalkyl    and heteroaryl radicals;-   R³⁰, R³¹ and R³² independently represent radicals as defined for R¹,    or one of R¹ and R³⁰ together with one of R³¹ and R³² and the carbon    atoms to which they are attached form a cycloalkyl radical;-   R³³ and R³⁴ independently represent hydrogen and radicals as defined    for R³, or R³³ and R³⁴ together with X′ represent cycloalkyl, aryl,    heterocyclyl and heteroaryl radicals, provided that when X′ is O,    R³⁴ is absent;-   x represents 1 or 2;-   X′ represents N, O and C(R¹⁷) wherein R¹⁷ represents hydrogen and    alkyl radicals;-   n represents an integer of from 0 to 6;-   t represents 0, 1 or 2; and-   Y and Y′ independently represent O, S and NR¹⁵ wherein R¹⁵    represents hydrogen and radicals as defined for R³.

Examples of compounds of the present invention as defined by Formula Iinclude:

-   1)    4-[3-[[[[(1-carboxyethyl)amino]sulfonyl](2-methylpropyl)amino]-2R-hydroxy-1S-(phenylmethyl)-propyl]amino]-2,2,3R-trimethyl-4-oxobutanoic    acid-   2)    4-[3-[[[[(1-carboxy-1-methylethyl)amino]sulfonyl]-(4-pyridinylmethyl)amino]-2R-hydroxy-1S-(phenylmethyl)propyl]amino]-3R-methyl-4-oxobutanoic    acid-   3)    N-[[[3S-[(4-amino-2R,3,3-trimethyl-1,4-dioxobutyl)amino]-2R-hydroxy-4-phenylbutyl](3-methylbutyl)amino]sulfonyl]-2-methylalanine-   4)    1-[[[[3S-[(4-amino-2R,3,3-trimethyl-1,4-dioxobutyl)amino]-2R-hydroxy-4-phenylbutyl](3-methylbutyl)    amino]sulfonyl]amino]cyclopentane-carboxylic acid-   5)    phenylmethyl-4-[2R-hydroxy-3-[[[(2-hydroxy-1,1-dimethylethyl)amino]sulfonyl](2-methylpropyl)-amino]-1S-(phenylmethyl)propyl]-2,3R-dimethyl-4-oxobutanoate-   6)    3-[[[[3S-[(4-amino-2R-methyl-1,4-dioxobutyl)amino]-2R-hydroxy-4-phenylbutyl](2-methylpropyl)amino]sulfonyl]amino]-3-methylbutanoic    acid-   7)    phenylmethyl-4-[[3-[[[(1-carboxy-1-methylethyl)-methylamino]sulfonyl](2-methylpropyl)    amino]-2R-hydroxy-1S-(phenylmethyl)propyl]amino]-2,2,3R-trimethyl-4-oxobutanoate-   8)    4-[[3-[[[(2-carboxypropyl)amino]sulfonyl](2-methylpropyl)amino]-2R-hydroxy-1S-(phenylmethyl)-propyl]amino]-2,3R-dimethyl-4-oxobutanoic    acid-   9)    1-[[[(4-fluorophenyl)methyl][[3S-[2R-ethyl-3,3-dimethyl-1,4-dioxo-4-(phenylmethoxy)butyl]-2R-hydroxy-4-phenylbutyl]amino]sulfonyl]amino]-cyclopropanecarboxylic    acid-   10)    1-[[[[2R-hydroxy-3S-[(4-methoxy-2R,3,3-trimethyl-1,4-dioxobutyl)amino]-4-phenylbutyl](3-methylbutyl)amino]sulfonyl]amino]cyclopropanecarboxylic    acid

A family of compounds of particular interest within Formula I arecompounds embraced by Formula II:

wherein:

-   R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,    —CH₂C(O)NHCH₃, —C(CH 3)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),    —C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl and    cycloalkyl radicals, and amino acid side chains selected from    asparagine, S-methyl cysteine methionine and the sulfoxide (SO) and    sulfone (SO₂) derivatives thereof, isoleucine, allo-isoleucine,    alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine,    norleucine, glutamine, threonine, glycine, allo-threonine, serine,    O-methyl serine, aspartic acid, beta-cyanoalanine and valine side    chains;-   R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl    radicals, which radicals are optionally substituted with a group    selected from alkyl and halogen radicals, —NO₂, —C≡N, CF₃, —OR⁹,    —SR⁹, wherein R⁹ represents hydrogen and alkyl radicals;-   R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,    alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,    heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl,    aminoalkyl and mono- and disubstituted aminoalkyl radicals, wherein    said substituents are selected from alkyl, aryl, aralkyl,    cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,    heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case    of a disubstituted aminoalkyl radical, said substituents along with    the nitrogen atom to which they are attached, form a    heterocycloalkyl or a heteroaryl radical, and thioalkyl,    alkylthioalkyl and arylthioalkyl radicals and the sulfone and    sulfoxide derivatives thereof;-   R4 represents hydrogen and radicals as defined by R³;-   R⁷ and R^(7′) independently represent radicals as defined for R³ and    amino acid side chains selected from the group consisting of valine,    isoleucine, glycine, alanine, allo-isoleucine, asparagine, leucine,    glutamine, and t-butylglycine or R⁷ and R^(7′) together with the    carbon atom to which they are attached form a cycloalkyl radical;-   R⁸ represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl,    aralkyl, heterocycloalkyl and heteroaryl radicals and radicals    represented by the formulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶, SR¹⁶,    CONR¹⁶R¹⁷, CF₃ and NR¹⁶R¹⁷;-   wherein R¹⁶ and R¹⁷ independently represent hydrogen and radicals as    defined for R³, or R¹⁶ and R¹⁷ together with a nitrogen to which    they are attached in the formula NR¹⁶R¹⁷ represent heterocycloalkyl    and heteroaryl radicals;-   R³⁰, R³¹ and R³² independently represent radicals as defined for R¹,    or one of R¹ and R³⁰ together with one of R³¹ and R³² and the carbon    atoms to which they are attached form a cycloalkyl radical;-   R³³ and R³⁴ independently represent hydrogen and radicals as defined    for R³, or R³³ and R³⁴ together with the nitrogen atom to which they    are attached represent heterocycloalkyl and heteroaryl radicals;-   n represents an integer of from 0 to 6; and-   Y and Y′ independently represent O, S and NR¹⁵ wherein R¹⁵    represents hydrogen and radicals as defined for R³.

A more preferred family of compounds within Formula II consists ofcompounds wherein:

-   R¹ represents hydrogen and CH₂C(O)NHCH₃, C(CH₃)₂(SCH₃),    C(CH₃)₂(S[O]CH₃), C(CH₃)₂(S[O]₂CH₃), alkyl, alkenyl and alkynyl    radicals, and amino acid side chains selected from the group    consisting of asparagine, valine, threonine, allo-threonine,    isoleucine, tert-leucine, S-methyl cysteine and methionine and the    sulfone and sulfoxide derivatives thereof, alanine, and    allo-isoleucine;-   R² represents alkyl, cycloalkylalkyl and aralkyl radicals, which    radicals are optionally substituted with halogen radicals and    radicals represented by the formula —OR⁹ and —SR⁹ wherein R⁹    represents alkyl radicals;-   R³ represents alkyl, haloalkyl, alkenyl, alkoxyalkyl,    alkylthioalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,    heterocycloalkylalkyl, aryl, aralkyl and heteroaralkyl radicals;-   R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,    heteroaryl, aralkyl, heteroaralkyl, heterocycloalkyl and    heterocycloalkylalkyl radicals;-   R⁷ and R^(7′) independently represent alkyl and aralkyl radicals or    together with the carbon atom to which they are attached form a    cycloalkyl radical having from 3 to 8 carbon atoms;-   R⁸ represents alkylcarbonyl, aryl, aroyl, aryloxy, aralkanoyl,    cyano, hydroxycarbonyl, arylsulfonyl, alkylsulfonyl, alkylthio,    hydroxyl, alkoxy, heteroaryl, dialkylaminocarbonyl, dialkylamino,    cycloalkylamino, heterocyclylamino and alkoxycarbonyl radicals;-   R³⁰, R³¹ and R³² independently represent hydrogen and alkyl, alkenyl    and alkynyl radicals, or one of R¹ and R³⁰ together with one of R³¹    and R³² and the carbon atoms to which they are attached form a    cycloalkyl radical;-   R³³ and R³⁴ independently represent hydrogen and alkyl, alkenyl and    alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,    heterocycloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl    radicals;-   n is an integer of from 0 to 6; and-   Y and Y′ represent 0.

Of highest interest are compounds within Formula II wherein

-   R¹ represents hydrogen and CH₂C(O)NHCH₃, C(CH₃)₂(SCH₃),    C(CH₃)₂(S[O]CH₃), C(CH₃)₂(S[O]₂CH₃), methyl, ethyl, propargyl,    t-butyl, isopropyl and sec-butyl radicals, and amino acid side    chains selected from the group consisting of asparagine, valine,    S-methyl cysteine methionine, allo-iso-leucine, iso-leucine, and    beta-cyano alanine side chains;-   R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl, benzyl,    4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl radicals;-   R³ represents propyl, isoamyl, n-butyl, isobutyl, cyclohexyl,    cyclohexylmethyl, benzyl and pyridylmethyl radicals;-   R4 represents hydrogen and methyl, ethyl, i-propyl, n-propyl,    n-butyl, t-butyl, 1,1-dimethylpropyl and phenyl radicals;-   R⁷ and R^(7′) independently represent methyl, ethyl, propyl and    butyl radicals, or together with the carbon atom to which they are    attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl    radical;-   R⁸ represents methylcarbonyl, phenyl, hydroxy, methoxy, cyano,    methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,    t-butoxycarbonyl, benzyloxycarbonyl, carboxyl, methoxycarbonyl,    methylsulfonyl, methylthio, phenylsulfonyl, phenyl, 2-, 3- or    4-pyridyl, 2-, 3- or 4-pyridyl N-oxide, N,N-dimethylamino,    1-piperidinyl, 4-morpholinyl, 4-(N-methyl)piperazinyl and    1-pyrrolidinyl;-   R³⁰, R³¹ and R³² independently represent hydrogen and methyl, ethyl,    propyl, butyl, pentyl and hexyl radicals, or one of R¹ and R³⁰    together with one of R³¹ and R³² form a cycloalkyl radical having    from 3 to 8 carbon atoms;-   R³³ and R³⁴ independently represent hydrogen, methyl, ethyl, propyl,    isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl    radicals, cyclohexylmethyl, cyclohexyl, benzyl and naphthylmethyl    radicals;-   n represents an integer of from 0 to 0.6; and-   Y and Y′ represent 0.

Another family of compounds of particular interest within Formula I arecompounds embraced by Formula III:

wherein:

-   R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,    —CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),    —C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl and    cycloalkyl radicals, and amino acid side chains selected from    asparagine, S-methyl cysteine methionine and the sulfoxide (SO) and    sulfone (SO₂) derivatives thereof, isoleucine, allo-isoleucine,    alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine,    norleucine, glutamine, threonine, glycine, allo-threonine, serine,    aspartic acid, beta-cyano alanine and valine side chains;-   R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl    radicals, which radicals are optionally substituted with a group    selected from alkyl and halogen radicals, —NO₂, —C≡N, CF₃, —OR⁹,    —SR⁹, wherein R⁹ represents hydrogen and alkyl;-   R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,    alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,    heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl,    aminoalkyl and mono- and disubstituted aminoalkyl radicals, wherein    said substituents are selected from alkyl, aryl, aralkyl,    cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,    heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case    of a disubstituted aminoalkyl radical, said substituents along with    the nitrogen atom to which they are attached, form a    heterocycloalkyl or a heteroaryl radical, and thioalkyl,    alkylthioalkyl and arylthioalkyl radicals and the sulfone and    sulfoxide derivatives thereof;-   R4 represents hydrogen and radicals as defined for R³;-   R⁷ and R^(7′) independently represent radicals as defined for R³ and    amino acid side chains selected from the group consisting of valine,    isoleucine, glycine, alanine, allo-isoleucine, asparagine, leucine,    glutamine, and t-butylglycine or R⁷ and R^(7′) together with the    carbon atom to which they are attached form a cycloalkyl radical;-   R⁸ represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl,    aralkyl, heterocycloalkyl and heteroaryl radicals and radicals    represented by the formulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶, SR¹⁶,    CONR¹⁶R¹⁷, CF₃ and NR¹⁶R¹⁷;-   wherein R¹⁶ and R¹⁷ independently represent hydrogen and radicals as    defined for R³, or R¹⁶ and R¹⁷ together with a nitrogen to which    they are attached in the formula NR¹⁶R¹⁷ represent heterocycloalkyl    and heteroaryl radicals;-   R³⁰, R³¹ and R³² independently represent radicals as defined for R¹,    or one of R¹ and R³⁰ together with one of R³¹ and R³² and the carbon    atoms to which they are attached form a cycloalkyl radical;-   R³³ represents hydrogen and radicals as defined for R³; and-   n represents an integer of from 0 to 6.

A more preferred family of compounds within Formula III consists ofcompounds wherein

-   R¹ represents hydrogen, alkyl, alkenyl and alkynyl radicals, and    amino acid side chains selected from the group consisting of    asparagine, valine, threonine, allo-threonine, isoleucine,    tert-leucine, S-methyl cysteine methionine and the sulfone and    sulfoxide derivatives thereof, alanine, and allo-isoleucine;-   R² represents alkyl, cycloalkylalkyl and aralkyl radicals, which    radicals are optionally substituted with halogen radicals and    radicals represented by the formula —OR⁹ and —SR⁹ wherein R⁹    represents hydrogen and alkyl and halogen radicals;-   R³ represents alkyl, haloalkyl, alkenyl, alkoxyalkyl,    alkylthioalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,    heterocycloalkylalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl    radicals;-   R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,    heteroaryl, aralkyl, heteroaralkyl, heterocycloalkyl and    heterocycloalkylalkyl radicals;-   R⁷ and R^(7′) independently represent radicals as defined for R³ and    amino acid side chains selected from the group consisting of valine,    isoleucine, glycine, alanine, allo-isoleucine, asparagine, leucine,    glutamine, and t-butylglycine or R⁷ and R^(7′) together with the    carbon atom to which they are attached form a cycloalkyl radical;-   R⁸ represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl,    aralkyl, heterocycloalkyl and heteroaryl radicals and radicals    represented by the formulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶, SR¹⁶,    CONR¹⁶R¹⁷, CF₃ and NR¹⁶R¹⁷;-   wherein R¹⁶ and R¹⁷ independently represent hydrogen and radicals as    defined for R³, or R¹⁶ and R¹⁷ together with a nitrogen to which    they are attached in the formula NR¹⁶R¹⁷ represent heterocycloalkyl    and heteroaryl radicals;-   R³⁰, R³¹ and R³² independently represent hydrogen and alkyl, alkenyl    and alkynyl radicals, or one of R¹ and R³⁰ together with one of R³¹    and R³² and the carbon atoms to which they are attached form a    cycloalkyl radical;-   R³³ represents hydrogen and alkyl, alkenyl and alkynyl,    hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,    heterocycloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl    radicals; and-   n represents an integer of from 0 to 6.

Of highest interest are compounds within Formula III wherein

-   R¹ represents hydrogen, methyl, ethyl, propargyl, t-butyl, isopropyl    and sec-butyl radicals, and amino acid side chains selected from the    group consisting of asparagine, valine, S-methyl cysteine    methionine, allo-iso-leucine, iso-leucine, threonine, serine,    aspartic acid, beta-cyano alanine, and allo-threonine side chains;-   R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl, benzyl,    4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl radicals;-   R³ represents propyl, isobutyl, isoamyl, n-butyl, cyclohexyl,    cyclohexylmethyl, benzyl and pyridylmethyl radicals;-   R4 represents hydrogen and methyl, ethyl, i-propyl, propyl, n-butyl,    t-butyl, 1,1-dimethylpropyl and phenyl radicals, or R⁴ and R⁵    together with the nitrogen atom to which they are bonded form a    pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl radical;-   R⁷ and R^(7′) independently represent methyl, ethyl, propyl and    butyl radicals, or together with the carbon atom to which they are    attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl    radical; R⁸ represents methylcarbonyl, phenyl, hydroxy, methoxy,    cyano, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,    t-butoxycarbonyl, benzyloxycarbonyl, carboxyl, methoxycarbonyl,    methylsulfonyl, methylthio, phenylsulfonyl, phenyl, 2-, 3- or    4-pyridyl, 2-, 3- or 4-pyridyl N-oxide, N,N-dimethylamino,    1-piperidinyl, 4-morpholinyl, 4-(N-methyl)piperazinyl and    1-pyrrolidinyl.-   R³⁰, R³¹ and R³² independently represent hydrogen and methyl, ethyl,    propyl, butyl, pentyl and hexyl radicals, or one of R¹ and R³⁰    together with one of R³¹ and R³² form a cycloalkyl radical having    from 3 to 8 carbon atoms;-   R³³ represents hydrogen and methyl, ethyl, propyl, isopropyl, butyl,    isobutyl, tertiary butyl, pentyl and hexyl radicals,    cyclohexylmethyl, cyclohexyl, benzyl and naphthylmethyl radicals;    and-   n represents an integer of from 0 to 6.

As utilized herein, the term “alkyl”, alone or in combination, means astraight-chain or branched-chain alkyl radical containing from 1 toabout 10, preferably from 1 to 8, carbon atoms. Examples of suchradicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. Theterm “alkenyl”, alone or in combination, means a straight-chain orbranched-chain hydrocarbon radial having one or more double bonds andcontaining from 2 to about 18 carbon atoms preferably from 2 to 8 carbonatoms. Examples of suitable alkenyl radicals include ethenyl, propenyl,1,4-butadienyl, 12-octadecene and the like. The term “alkynyl”, alone orin combination, means a straight-chain hydrocarbon radical having one ormore triple bonds and containing from 2 to about 10 carbon atoms,preferably from 2 to 8 carbon atoms. Examples of alkynyl radicalsinclude ethynyl, propynyl, (propargyl), butynyl and the like. The term“alkoxy”, alone or in combination, means an alkyl ether radical whereinthe term alkyl is as defined above. Examples of suitable alkyl etherradicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy and the like. The term “cycloalkyl”,alone or in combination, means a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl radical wherein each cyclicmoiety contains from about 3 to about 8 carbon atoms and is cyclic. Theterm “cycloalkylalkyl” means an alkyl radical as defined above which issubstituted by a cycloalkyl radical containing from about 3 to about 8,preferably from 3 to 6 carbon atoms. Examples of such cycloalkylradicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andthe like. The term “aryl”, alone or in combination, means a phenyl ornaphthyl radical which optionally carries one or more substituentsselected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano,haloalkyl and the like, such as phenyl, p-tolyl, 4-methoxyphenyl,4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl,1-naphthyl, 2-naphthyl, and the like. The term “aralkyl”, alone or incombination, means an alkyl radical as defined above in which onehydrogen atom is replaced by an aryl radical as defined above, such asbenzyl, 2-phenylethyl and the like. The term “aralkoxy carbonyl”, aloneor in combination, means a radical of the formula —C(O)—O-aralkyl inwhich the term “aralkyl” has the significance given above. An example ofan aralkoxycarbonyl radical is benzyloxycarbonyl. The term “aryloxy”means a radical of the formula aryl-O— in which the term aryl has thesignificance given above. The term “alkanoyl”, alone or in combination,means an acyl radical derived from an alkanecarboxylic acid whereinalkane means a radical as defined above for alkyl. Examples of alkanoylradicals include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl,and the like. The term “cycloalkylcarbonyl” means an acyl group derivedfrom a monocyclic or bridged cycloalkanecarboxylic acid such ascyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and thelike, or from a benz-fused monocyclic cycloalkanecarboxylic acid whichis optionally substituted by, for example, alkanoylamino, such as1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The term “aralkanoyl”, meansan acyl radical derived from an aryl-substituted alkanecarboxylic acidsuch as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl),4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl,4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl, and the like. The term“aroyl” means an acyl radical derived from an aromatic carboxylic acid.Examples of such radicals include aromatic carboxylic acids, anoptionally substituted benzoic or naphthoic acid such as benzoyl,4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl,1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl,6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.The heterocyclyl or heterocycloalkyl portion of a heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, or heterocyclyalkylgroup or the like is a saturated or partially unsaturated monocyclic,bicyclic or tricyclic heterocycle which contains one or more heteroatoms selected from nitrogen, oxygen and sulphur, which is optionallysubstituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo,and the like, and/or on a secondary nitrogen atom (i.e., —NH—) by alkyl,aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiarynitrogen atom (i.e. ═N—) by oxido and which is attached via a carbonatom. The heteroaryl portion of a heteroaroyl, heteroaryloxycarbonyl, ora heteroaralkoxy carbonyl group or the like is an aromatic monocyclic,bicyclic, or tricyclic heterocycle which contains the hetero atoms andis optionally substituted as defined above with respect to thedefinition of heterocyclyl. Such heterocyclyl and heteroaryl radicalshave from four to about 12 ring members, preferably from 4 to 10 ringmembers. Examples of such heterocyclyl and heteroaryl groups arepyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl,pyrrolyl, imidazolyl (e.g., imidazol 4-yl,1-benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, furyl, thienyl, triazolyl, oxazolyl, thiazolyl, indolyl(e.g., 2-indolyl, etc.), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl,1-oxido-2-quinolinyl, etc.), isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, etc.), tetrahydroquinolinyl (e.g.,1,2,3,4-tetrahydro-2-quinolyl, etc.), 1,2,3,4-tetrahydroisoquinolinyl(e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, etc.), quinoxalinyl,β-carbolinyl, 2-benzofurancarbonyl, 1-, 2-, 4- or 5-benzimidazolyl, andthe like. The term “cycloalkylalkoxycarbonyl” means an acyl groupderived from a cycloalkylalkoxycarboxylic acid of the formulacycloalkylalkyl-O—COOH wherein cycloalkylalkyl has the significancegiven above. The term “aryloxyalkanoyl” means an acyl radical of theformula aryl-O-alkanoyl wherein aryl and alkanoyl have the significancegiven above. The term “heterocyclyloxycarbonyl” means an acyl groupderived from heterocyclyl-O—COOH wherein heterocyclyl is as definedabove. The term “heterocyclylalkanoyl” is an acyl radical derived from aheterocyclyl-substituted alkane carboxylic acid wherein heterocyclyl hasthe significance given above. The term “heterocyclylalkoxycarbonyl”means an acyl radical derived from a heterocyclyl-substitutedalkane-O—COOH wherein heterocyclyl has the significance given above. Theterm “heteroaryloxycarbonyl”, means an acyl radical derived from acarboxylic acid represented by heteroaryl-O—COOH wherein heteroaryl hasthe significance given above. The term “aminocarbonyl” alone or incombination, means an amino-substituted carbonyl (carbamoyl) groupderived from an amino-substituted carboxylic acid wherein the aminogroup can be a primary, secondary or tertiary amino group containingsubstituents selected from hydrogen, and alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl radicals and the like. The term“aminoalkanoyl” means an acyl group derived from an amino-substitutedalkanecarboxylic acid wherein the amino group can be a primary,secondary or tertiary amino group containing substituents selected fromhydrogen, and alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicalsand the like. The term “halogen” means fluorine, chlorine, bromine oriodine. The term “haloalkyl” means an alkyl radical having thesignificance as defined above wherein one or more hydrogens are replacedwith a halogen. Examples of such haloalkyl radicals includechloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1,1,1-trifluoroethyl and the like. The term “leavinggroup” generally refers to groups readily displaceable by a nucleophile,such as an amine, a thiol or an alcohol nucleophile. Such leaving groupsare well known in the art. Examples of such leaving groups include, butare not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole,halides, triflates, tosylates and the like. Preferred leaving groups areindicated herein where appropriate.

Procedures for preparing the compounds of Formula I are set forth below.It should be noted that the general procedure is shown as it relates topreparation of compounds having the specified stereochemistry, forexample, wherein the absolute stereochemistry about the hydroxyl groupis designated as (R), which is the preferred stereochemistry for thecompounds of the present invention. However, such procedures aregenerally applicable to those compounds of opposite configuration, e.g.,where the stereochemistry about the hydroxyl group is (S). In addition,the compounds having the (R) stereochemistry can be utilized to producethose having the (S) stereochemistry. For example, a compound having the(R) stereochemistry can be inverted to the (S) stereochemistry usingwell-known methods.

Preparation of Compounds of Formula I

The compounds of the present invention represented by Formula I abovecan be prepared utilizing the following general procedure. Thisprocedure is schematically shown in the following Schemes I and II:

a) amine b) sulfamoyl chloride R⁸(CH₂)_(n)C(R⁷R^(7′))N(R⁴)SO₂Cl (oranhydride)+acid scavenger c) deprotection d) coupling

a) amine b) sulfamoyl chloride R⁸(CH₂)_(n)C(R⁷R^(7′))N(R⁴)SO₂Cl (oranhydride)+acid scavenger c) deprotection d) coupling

An N-protected chloroketone derivative of an amino acid having theformula:

wherein P represents an amino protecting group, and R² is as definedabove, is reduced to the corresponding alcohol utilizing an appropriatereducing agent. Suitable amino protecting groups are well known in theart and include carbobenzoxy, t-butoxycarbonyl, and the like. Apreferred amino protecting group is carbobenzoxy. A preferredN-protected chloroketone is N-benzyloxycarbonyl-L-phenylalaninechloromethyl ketone. A preferred reducing agent is sodium borohydride.The reduction reaction is conducted at a temperature of from −10° C. toabout 25° C., preferably at about 0° C., in a suitable solvent systemsuch as, for example, tetrahydrofuran, and the like. The N-protectedchloroketones are commercially available, e.g., such as from Bachem,Inc., Torrance, Calif. Alternatively, the chloroketones can be preparedby the procedure set forth in S. J. Fittkau, J. Prakt. Chem., 315, 1037(1973), and subsequently N-protected utilizing procedures which are wellknown in the art.

The halo alcohol can be utilized directly, as described below, or,preferably, is then reacted, preferably at room temperature, with asuitable base in a suitable solvent system to produce an N-protectedamino epoxide of the formula:

wherein P and R² are as defined above. Suitable solvent systems forpreparing the amino epoxide include ethanol, methanol, isopropanol,tetrahydrofuran, dioxane, and the like including mixtures thereof.Suitable bases for producing the epoxide from the reduced chloroketoneinclude potassium hydroxide, sodium hydroxide, potassium t-butoxide, DBUand the like. A preferred base is potassium hydroxide.

Alternatively, a protected amino epoxide can be prepared starting withan L-amino acid which is reacted with a suitable amino-protecting groupin a suitable solvent to produce an amino-protected L-amino acid esterof the formula:

wherein P¹ and P² independently represent hydrogen, benzyl andamino-protecting groups (as defined above), provided that P¹ and P² arenot both hydrogen; P³ represents carboxyl-protecting group, e.g.,methyl, ethyl, benzyl, tertiary-butyl and the like; and R² is as definedabove.

The amino-protected L-amino acid ester is then reduced, to thecorresponding alcohol. For example, the amino-protected L-amino acidester can be reduced with diisobutylaluminum hydride at −78° C. in asuitable solvent such as toluene. The resulting alcohol is thenconverted, for example, by way of a Swern oxidation, to thecorresponding aldehyde of the formula:

wherein P¹, P² and R² are as defined above. Thus, a dichloromethanesolution of the alcohol is added to a cooled (−75 to −68° C.) solutionof oxalyl chloride in dichloromethane and DMSO in dichloromethane andstirred for 35 minutes.

The aldehyde resulting from the Swern oxidation is then reacted with ahalomethyllithium reagent, which reagent is generated in situ byreacting an alkyllithium or arylithium compound with a dihalomethanerepresented by the formula X¹CH₂X² wherein X¹ and X² independentlyrepresent I, Br or Cl. For example, a solution of the aldehyde andchloroiodomethane in THF is cooled to −78° C. and a solution ofn-butyllithium in hexane is added. The resulting product is a mixture ofdiastereomers of the corresponding amino-protected epoxides of theformulas:

The diastereomers can be separated e.g., by chromatography, or,alternatively, once reacted in subsequent steps the diastereomericproducts can be separated. For compounds having the (S) stereochemistry,a D-amino acid can be utilized in place of the L-amino acid.

The amino epoxide is then reacted, in a suitable solvent system, with anequal amount, or preferably an excess of, a desired amine of theformula:R³NH₂wherein R³ is hydrogen or is as defined above. The reaction can beconducted over a wide range of temperatures, e.g., from about 10° C. toabout 100° C., but is preferably, but not necessarily, conducted at atemperature at which the solvent begins to reflux. Suitable solventsystems include protic, non-protic and dipolar aprotic organic solventssuch as, for example, those wherein the solvent is an alcohol, such asmethanol, ethanol, isopropanol, and the like, ethers such astetrahydrofuran, dioxane and the like, and toluene,N,N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. Apreferred solvent is isopropanol. Exemplary amines corresponding to theformula R³NH₂ include benzyl amine, isobutylamine, n-butyl amine,isopentyl amine, isoamylamine, cyclohexanemethyl amine, naphthylenemethyl amine and the like. The resulting product is a 3-(N-protectedamino)-3-(R²)-1-(NHR³)-propan-2-ol derivative (hereinafter referred toas an amino alcohol) can be represented by the formulas:

wherein P, P¹, P², R² and R³ are as described above. Alternatively, ahaloalcohol can be utilized in place of the amino epoxide.

The amino alcohol defined above is then reacted in a suitable solventwith a sulfamoyl halide, e.g. sulfamoyl chloride (R⁴R⁵NSO₂C¹ orR⁴HNSO₂Cl) or sulfamoyl anhydride in the presence of an acid scavenger.Suitable solvents in which the reaction can be conducted includemethylene chloride, tetrahydrofuran. Suitable acid scavengers includetriethylamine, pyridine. The resulting sulfamic acid derivative can berepresented, depending on the epoxide utilized, by the formulas;

wherein P, P¹, P², R², R³, R⁴, R⁵, R⁷, R^(7′), R⁸ and n are as definedabove. These intermediates are useful for preparing inhibitor compoundsof the present invention and are also active inhibitors of retroviralproteases.

The sulfamoyl halides of the formula [R⁸(CH₂)_(n)C(R⁷R^(7′))][R⁴]NSO₂X,wherein R4 is hydrogen can be prepared by the reaction of a suitableisocyanate of the formula [R⁸(CH₂)_(n)C(R⁷R^(7′))][R⁴]NCO with fumingsulfuric acid to produce the corresponding sulfamate which is thenconverted to the halide by well known procedures, such as by treatingthe sulfamate with PCl₅. Alternatively the isocyanate can be treatedwith chlorosulfonic acid to produce the corresponding sulfamoyl chloridedirectly.

The sulfamoyl halides of the formula [R⁸(CH₂)_(n)C(R⁷R^(7′))][R⁴]NSO₂Cl,wherein R⁴ is other than hydrogen, can be prepared by reacting an amineof the formula [R⁸(CH₂)_(n)C(R⁷R^(7′))][R⁴]NH, preferably as a salt suchas the hydrochloride, with sulfuryl chloride in a suitable solvent suchas acetonitrile. The reaction mixture is gradually warmed to refluxtemperature and maintained at the reflux temperature until the reactionis complete. Alternatively, sulfamoyl halides of the formula[R⁸(CH₂)_(n)C(R⁷R^(7′))][R⁴]NSO₂Cl can be prepared by reacting an amineof the fomula [R⁸(CH₂)_(n)C(R⁷R^(7′))][R⁴]NH with sulfuryl chloride inboiling MeCN as disclosed in Matier et al., J. Med. Chem., 15, No. 5, p.538 (1972).

Alternatively, the sulfamoyl halide can be prepared by reacting asulfamoyl halide derivative of an isocyanate, i.e., a derivative of theformula ClSO₂NCO with an appropriate alcohol of the formulaHOC(R⁷R^(7′))(CH₂)_(n)R⁸ to produce the corresponding compound of theformula ClSO₂NHC(O)OC(R⁷R^(7′))(CH₂)_(n)R⁸. Following deletion of thecarbonyl moiety a sulfamoyl halide of the formulaClSO₂NHC(R⁷R^(7′))(CH₂)_(n)R⁸ is produced. This procedure is describedin J. Org. Chem., 54, 5826-5828 (1989). Alternatively, the amino alcoholcan be reacted with a chlorosulfonyl methyl ester of the formula ClSO₂Oalkyl to produce the corresponding derivative and then reacted with anamine of the formula HNR⁴R⁵.

Following preparation of the sulfonyl urea derivative, the aminoprotecting group P or P¹ and P² amino protecting groups are removedunder conditions which will not affect the remaining portion of themolecule. These methods are well known in the art and include acidhydrolysis, hydrogenolysis and the like. A preferred method involvesremoval of the protecting group, e.g., removal of a carbobenzoxy group,by hydrogenolysis utilizing palladium on carbon in a suitable solventsystem such as an alcohol, acetic acid, and the like or mixturesthereof. Where the protecting group is a t-butoxycarbonyl group, it canbe removed utilizing an inorganic or organic acid, e.g., HCl ortrifluoroacetic acid, in a suitable solvent system, e.g., dioxane ormethylene chloride. Where the protecting group is a benzyl radical, itcan be removed by hydrogenolysis. The resulting product is the aminesalt derivative. Following neutralization of the salt, the amine is thenreacted with a succinic acid, or derivative thereof, as described below,to produce the antiviral compounds of the present invention having theformula:

wherein t, R¹, R², R³, R⁴, R⁷, R^(7′), R⁸, R³⁰, R³¹, R³², R³³ and R³⁴are as defined above.

Alternatively, the protected amino alcohol from the epoxide opening canbe further protected at the newly introduced amino group with aprotecting group P′ which is not removed when the first protecting P isremoved. One skilled in the art can choose appropriate combinations of Pand P′. One suitable choice is when P is Cbz and P′ is Boc. Theresulting compound represented by the formula:

can be carried through the remainder of the synthesis to provide acompound of the formula:

and the new protecting group P′ is selectively removed, and followingdeprotection, the resulting amine reacted to form the sulfamic acidderivative as described above. This selective deprotection andconversion to the sulfamic acid can be accomplished at either the end ofthe synthesis or at any appropriate intermediate step if desired.

To produce the succinic acid portion of the compounds of Formula I, thestarting material is a lactate of the formula:

wherein P″ represents alkyl and aralkyl radicals, such as, for example,ethyl, methyl, benzyl and the like. The hydroxyl group of the lactate isprotected as its ketal by reaction in a suitable solvent system withmethyl isopropenyl ether (1,2-methoxypropene) in the presence of asuitable acid. Suitable solvent systems include methylene chloride,tetrahydrofuran and the like as well as mixtures thereof. Suitable acidsinclude POCl₃ and the like. It should be noted that well-known groupsother than methyl isopropenyl ether can be utilized to form the ketal.The ketal is then reduced with diisobutylaluminum hydride (DIBAL) at−78° C. to produce the corresponding aldehyde which is then treated withethylidene triphenylphosphorane (Wittig reaction) to produce a compoundrepresented by the formula:

The ketal protecting group is then removed utilizing procedureswell-known in the art such as by mild acid hydrolysis. The resultingcompound is then esterified with isobutyryl chloride to produce acompound of the formula:

reaction mixture to room temperature to effect a Claisen rearrangement([3,3]) to produce the corresponding acid represented by the formula:

Those skilled in the art will recognize that variations on this schemeare possible, using either different protecting groups or reagents tocarry out the same transformations. One can also utilize other acidchlorides in place of isobutyryl chloride to prepare similar analogs.

Treatment of the acid with benzyl bromide in the presence of a tertiaryamine base, e.g., DBU, produces the corresponding ester which is thencleaved oxidatively to give a trisubstituted succinic acid:

The trisubstituted succinic acid is then coupled to the sulfamateisostere utilizing procedures well known in the art. To produce the freeacid, the benzyl ester is removed by hydrogenolysis to produce thecorresponding acid. The acid can then be converted to the primary amideby methods well-known in the art. The resulting product is a compoundrepresented by Formula I.

An alternative method for preparing trisubstituted succinic acidsinvolves reacting an ester of acetoacetic acid represented by theformula:

where R is a suitable protecting group, such as methyl, ethyl, benzyl ort-butyl with sodium hydride and a hydrocarbyl halide (R³¹X or R³²X) in asuitable solvent, e.g., THF, to produce the corresponding disubstitutedderivative represented by the formula:

This disubstituted acetoacetic acid derivative is then treated withlithium diisopropyl amide at about −10° C. and in the presence ofPhN(triflate)₂ to produce a vinyl triflate of the formula:

The vinyl triflate is then carbonylated utilizing a palladium catalyst,e.g., Pd(OAc)₂ and Ph₃P, in the presence of an alcohol (R′OH) or water(R″═H) and a base, e.g., triethylamine, in a suitable solvent such asDMF, to produce the olefinic ester or acid of the formula:

The olefin can then be subsequently asymmetrically hydrogenated, asdescribed below, to produce a trisubstituted succinic acid derivative ofthe formula:

If R″ is not H, R″ can be removed by either hydrolysis, acidolysis, orhydrogenolysis, to afford the corresponding acid, which is then coupledto the sulfamate isostere as described above and then, optionally, the Rgroup removed to produce the corresponding acid, and optionally,converted to the amide.

Alternatively, one can react the sulfamate isostere with either asuitably monoprotected succinic acid or glutaric acid of the followingstructure;

followed by removal of the protecting group and conversion of theresulting acid to an amide. One can also react an anhydride of thefollowing structure;

with the sulfamate isostere and then separate any isomers or convert theresulting acid to an amide and then separate any isomers.

It is contemplated that for preparing compounds of the Formulas havingR⁶, the compounds can be prepared following the procedure set forthabove and, prior to coupling the sulfamate derivative or analog thereof,e.g. coupling to the amino acid PNH(CH₂)_(t)CH(R¹)COOH, carried througha procedure referred to in the art as reductive amination. Thus, asodium cyanoborohydride and an appropriate aldehyde or ketone can bereacted with the sulfamate derivative compound or appropriate analog atroom temperature in order to reductively aminate any of the compounds ofFormulas I-IV. It is also contemplated that where R³ of the aminoalcohol intermediate is hydrogen, the inhibitor compounds of the presentinvention wherein R³ is alkyl, or other substituents wherein the α-Ccontains at least one hydrogen, can be prepared through reductiveamination of the final product of the reaction between the amino alcoholand the amine or at any other stage of the synthesis for preparing theinhibitor compounds.

Contemplated equivalents of the general formulas set forth above for theantiviral compounds and derivatives as well as the intermediates arecompounds otherwise corresponding thereto and having the same generalproperties, such as tautomers thereof as well as compounds, wherein oneor more of the various R groups are simple variations of thesubstituents as defined therein, e.g., wherein R is a higher alkyl groupthan that indicated. In addition, where a substituent is designated as,or can be, a hydrogen, the exact chemical nature of a substituent whichis other than hydrogen at that position, e.g., a hydrocarbyl radical ora halogen, hydroxy, amino and the like functional group, is not criticalso long as it does not adversely affect the overall activity and/orsynthesis procedure.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable from known starting materials.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

All reagents were used as received without purification. All proton andcarbon NMR spectra were obtained on either a Varian VXR-300 or VXR-400nuclear magnetic resonance spectrometer.

The following Examples 1 through 10 illustrate preparation ofintermediates. These intermediates are useful in preparing the inhibitorcompounds of the present invention.

EXAMPLE 1

Preparation ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]-N-isoamylamine

Part A:

To a solution of 75.0 g (0.226 mol) ofN-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of807 mL of methanol and 807 mL of tetrahydrofuran at −2° C., was added13.17 g (0.348 mol, 1.54 equiv.) of solid sodium borohydride over onehundred minutes. The solvents were removed under reduced pressure at 40°C. and the residue dissolved in ethyl acetate (approx. 1 L). Thesolution was washed sequentially with 1M potassium hydrogen sulfate,saturated sodium bicarbonate and then saturated sodium chloridesolutions. After drying over anhydrous magnesium sulfate and filtering,the solution was removed under reduced pressure. To the resulting oilwas added hexane (approx. 1 L) and the mixture warmed to 60° C. withswirling. After cooling to room temperature, the solids were collectedand washed with 2 L of hexane. The resulting solid was recrystallizedfrom hot ethyl acetate and hexane to afford 32.3 g (43% yield) ofN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp150-151° C. and M+Li⁺=340.

Part B:

To a solution of 6.52 g (0.116 mol, 1.2 equiv.) of potassium hydroxidein 968 mL of absolute ethanol at room temperature, was added 32.3 g(0.097 mol) of N-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol. Afterstirring for fifteen minutes, the solvent was removed under reducedpressure and the solids dissolved in methylene chloride. After washingwith water, drying over magnesium sulfate, filtering and stripping, oneobtains 27.9 g of a white solid. Recrystallization from hot ethylacetate and hexane afforded 22.3 g (77% yield) ofN-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane, mp 102-103°C. and MH⁺ 298.

Part C:

A solution of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (1.00 g, 3.36 mmol) andisoamylamine (4.90 g, 67.2 mmol, 20 equiv.) in 10 mL of isopropylalcohol was heated to reflux for 1.5 hours. The solution was cooled toroom temperature, concentrated in vacuo and then poured into 100 mL ofstirring hexane whereupon the product crystallized from solution. Theproduct was isolated by filtration and air dried to give 1.18 g, 95% ofN=[[3(S)-phenylmethylcarbamoyl)amino-2(R)-hydroxy-4-phenylbutyl]N-[(3-methylbutyl)]aminemp 108.0-109.5° C., MH⁺ m/z 371.

EXAMPLE 2

Preparation of N,N-dibenzyl-3(S)-amino-1,2-(S)-epoxy-4-phenylbutane

Step A:

A solution of L-phenylalanine (50.0 g, 0.302 mol), sodium hydroxide(24.2 g, 0.605 mol) and potassium carbonate (83.6 g, 0.605 mol) in water(500 ml) is heated to 97° C. Benzyl bromide (108.5 ml, 0.912 mol) isthen slowly added (addition time ˜25 min). The mixture is then stirredat 97° C. for 30 minutes. The solution is cooled to room temperature andextracted with toluene (2×250 ml). The combined organic layers are thenwashed with water, brine, dried over magnesium sulfate, filtered andconcentrated to give an oil product. The crude product is then used inthe next step without purification.

Step B:

The crude benzylated product of the above step is dissolved in toluene(750 ml) and cooled to −55° C. A 1.5 M solution of DIBAL-H in toluene(443.9 ml, 0.666 mol) is then added at a rate to maintain thetemperature between −55° to −50° C. (addition time −1 hour). The mixtureis stirred for 20 minuses at −55° C. The reaction is quenched at −55° C.by the slow addition of methanol (37 ml). The cold solution is thenpoured into cold (5° C.) 1.5 N HCl solution (1.8 L). The precipitatedsolid (approx. 138 g) is filtered off and washed with toluene. The solidmaterial is suspended in a mixture of toluene (400 ml) and water (100ml). The mixture is cooled to 5° C., treated with 2.5 N NaOH (186 ml)and then stirred at room temperature until the solid is dissolved. Thetoluene layer is separated from the aqueous phase and washed with waterand brine, dried over magnesium sulfate, filtered and concentrated to avolume of 75 ml (89 g). Ethyl acetate (25 ml) and hexane (25 ml) arethen added to the residue upon which the alcohol product begins tocrystallize. After 30 min., an additional 50 ml hexane is added topromote further crystallization. The solid is filtered off and washedwith 50 ml hexane to give approximately 35 g of material. A second cropof matrial can be isolated by refiltering the mother liquor. The solidsare combined and recrystallized from ethyl acetate (20 ml) and hexane(30 ml) to give, in 2 crops, approximately 40 g (40% fromL-phenylalanine) of analytically pure alcohol product. The motherliquors are combined and concentrated (34 g). The residue is treatedwith ethyl acetate and hexane which provides an additional 7 g (˜7%yield) of slightly impure solid product. Further optimization in therecovery from the mother liquor is probable.

Step C:

A solution of oxalyl chloride (8.4 ml, 0.096 mol) in dichloromethane(240 ml) is cooled to −74° C. A solution of DMSO (12.0 ml, 0.155 mol) indichloromethane (50 ml) is then slowly added at a rate to maintain thetemperature at −74° C. (addition time ˜1.25 hr). The mixture is stirredfor 5 min. followed by addition of a solution of the alcohol (0.074 mol)in 100 ml of dichloromethane (addition time −20 min., temp. −75° C. to−68° C.). The solution is stirred at −78° C. for 35 minutes.Triethylamine (41.2 ml, 0.295 mol) is then added over 10 min. (temp.−78° to −68° C.) upon which the ammonium salt precipitated. The coldmixture is stirred for 30 min. and then water (225 ml) is added. Thedichloromethane layer is separated from the aqueous phase and washedwith water, brine, dried over magnesium sulfate, filtered andconcentrated. The residue is diluted with ethyl acetate and hexane andthen filtered to further remove the ammonium salt. The filtrate isconcentrated to give the desired aldehyde product. The aldehyde wascarried on to the next step without purification.

Temperatures higher than −70° C. have been reported in the literaturefor the Swern oxidation. Other Swern modifications and alternatives tothe Swern oxidations are also possible.

A solution of the crude aldehyde 0.074 mol and chloroiodomethane (7.0ml, 0.096 mol) in tetrahydrofuran (285 ml) is cooled to −78° C. A 1.6 Msolution of n-butyllithium in hexane (25 ml, 0.040 mol) is then added ata rate to maintain the temperature at −75° C. (addition time −15 min.).After the first addition, additional chloroiodomethane (1.6 ml, 0.022mol) is added again, followed by n-butyllithium (23 ml, 0.037 mol),keeping the temperature at −75° C. The mixture is stirred for 15 min.Each of the reagents, chloroiodomethane (0.70 ml, 0.010 mol) andn-butyllithium (5 ml, 0.008 mol) are added 4 more times over 45 min. at−75° C. The cooling bath is then removed and the solution warmed to 22°C. over 1.5 hr. The mixture is poured into 300 ml of saturated aq.ammonium chloride solution. The tetrahydrofuran layer is separated. Theaqueous phase is extracted with ethyl acetate (1×300 ml). The combinedorganic layers are washed with brine, dried over magnesium sulfate,filtered and concentrated to give a brown oil (27.4 g). The productcould be used in the next step without purification. The desireddiastereomer can be purified by recrystallization at a subsequent step.

Alternately, the product could be purified by chromatography.

EXAMPLE 3

Preparation ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenyl]N-isobutylamine

A solution of N-benzyloxycarbonyl-3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (50.0 g, 0.168 mol) and isobutylamine (246 g, 3.24 mol, 20equivalents) in 650 mL of isopropyl alcohol was heated to reflux for1.25 hours. The solution was cooled to room temperature, concentrated invacuo and then poured into 1 L of stirring hexane whereupon the productcrystallized from solution. The product was isolated by filtration andair dried to give 57.56 g, 92% ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenyl]N-isobutylamine, mp108.0-109.5° C., MH+ m/z=371.

EXAMPLE 4

Preparation of Sulfamoyl Chlorides

Method A:

An amino acid ester hydrochloride (1 mmol) is suspended in a suitablesolvent such as hexane, dichloromethane, toluene and the like, but mostpreferable acetonitrile. To the well stirred mixture is added sulfurylchloride (3 mmol) in a suitable solvent, or neat, dropwise over severalminutes. The reaction is allowed to stir at zero to reflux temperatures,preferable at reflux, for 1 to 48 hours, preferably for 24 hours. Thesolvent is removed and the residue triturated with a suitable solvent,such as hexane, pentane, toluene, but most preferably diethyl ether. Thesolvent is decanted and concentrated. The product may then be utilizedas such or purified by distillation or in the case of solidsrecrystallized from appropriate solvents.

Method B:

An alpha-hydroxy ester (1 mmol) is dissolved in an appropriate solventsuch as acetonitrile, dichloromethane, toluene and the like, but mostpreferable hexane. Chlorosulfonyl isocyanate (1 mmol) added neat or in asolvent, preferably in hexane, is added dropwise. The reaction isstirred from zero to reflux, preferably at reflux, for 5 minutes toseveral hours, preferably for 1 hour. The solvent is then removed andthe residue used as such, or taken up in an appropriate solvent,expecially dichloromethane, and filtered to remove any impurities. Theproduct may then be purified by distillation or in the case of solidsrecrystallized from appropriate solvents.

EXAMPLE 5

Preparation of Sulfamates

An amino alcohol as prepared in Example 3 (1 mmol) and a suitable base,such as triethylamine, pyridine, sodium carbonate, and the like,preferably diisopropylethylamine (1 mmol) are dissolved in a suitablesolvent such as ether, chloroform, acetronitrile and the like, butpreferably dichloromethane. The sulfamoyl chloride from part A or B ofExample 4, neat or dissolved in an appropriate solvent, is added to theabove solution. The reaction is stirred at zero to reflux temperatures,but preferably at room temperature for 1 to 48 hours. The product can bepurified by silica gel chromotography or by an extractive workupfollowed by recrystallization.

EXAMPLE 6

Following the procedures of the previous Examples 1-5, the intermediatecompounds set forth in Tables 1A and 1B could be prepared. TABLE 1A

R³ R¹⁶ R⁴ isobutyl CH₃ CH₃ isoamyl CH₃ CH₃ p-F benzyl CH₃ CH₃ isobutylCH₃ H isobutyl CH₂CH₂CH₂CH₃ H isobutyl CH(CH₃)₂ H isobutyl C(CH₃)₃ Hisobutyl C₆H₅ H

TABLE 1B

Entry R⁴ R¹⁶ 1 CH₃ CH₃ 2 H CH₃ 3 H (CH₂)₃CH₃ 4 H CH(CH₃)₂ 5 H C(CH₃)₃

The following Examples 7-10 illustrate preparation of succinoylcompounds. These intermediates can be coupled to the intermediatecompounds of Examples 1-6 to produce inhibitor compounds of the presentinvention.

EXAMPLE 7

Preparation of Benzyl 2,2,3(R)-trimethylsuccinate PART A: Preparation ofMethyl (S)-lactate, 2-methoxy-2-propyl ether

To a mixture of methyl(S)-(−)-lactate (13.2 g, 100 mmol) and,2-methoxypropene (21.6 g, 300 mmol) in CH₂Cl₂ (150 ml) was added POCl₃(7 drops) at r.t. and the resulting mixture was stirred at thistemperature for 16 hours. After the addition of Et₃N (10 drops), thesolvents were removed in vacuo to give 20.0 g of (98%) desired product.

PART B: Preparation of 2(S)-hydroxypropanal, 2-methoxy-2-propyl ether

To a solution of compound from Part A (20.0 g) in CH₂Cl₂ (100 ml) wasadded DIBAL (65 ml of 1.5M solution in toluene, 97.5 mmol) dropwise at−78° C. for 45 min., then stirring was continued at this temperature foranother 45 min. To this cold solution was added MeOH (20 ml), saturatedNaCl solution (10 ml) and allowed the reaction mixture to warm up tor.t. and diluted with ether (200 ml), MgSO₄ (150 g) was added andstirred for another 2 h. The mixture was filtered and the solid waswashed twice with ether. The combined filtrates were rotavaped to afford11.2 g (78%) of the desired aldehyde.

PART C: Preparation of 2(S)-hydroxy-cis-3-butene, 2-methoxy-2-propylether

To a suspension of ethyltriphenylphosphonium bromide (28 g, 75.5 mmol)in THF (125 ml) was added KN (TMS)₂ (15.7 g, 95%, 75 mmol) in portionsat 0° C. and stirred for 1 h at the temperature. This red reactionmixture was cooled to −78° C. and to this was added a solution ofaldehyde from Part B (11 g, 75 mmol) in THF (25 ml). After the additionwas completed, the resulting reaction mixture was allowed to warm up tor.t. and stirred for 16 h. To this mixture was added saturated NH₄Cl(7.5 ml) and filtered through a pad of celite with a thin layer ofsilica gel on the top. The solid was washed twice with ether. Thecombined filtrates were concentrated in vacuo to afford 11.5 g of crudeproduct. The purification of crude product by flash chromatography(silica gel, 10:1 Hexanes/EtoAc) affording 8.2 g (69%) pure alkene.

PART D: Preparation of 2(S)-hydroxy-cis-3-butene

A mixture of alkene from Part C (8.2 g) and 30% aqueous acetic acid (25ml) was stirred at r.t. for 1 hour. To this mixture was added NaHCO₃slowly until the pH was ˜7, then extracted with ether (10 ml×5). Thecombined ether solutions were dried (Na₂SO₄) and filtered. The filtratewas distilled to remove the ether to give 2.85 g (64%) pure alcohol,m/e=87 (M+H).

PART E: Preparation of 2,2,3-trimethyl-hex-(trans)-4-enoic acid

To a mixture of alcohol from Part D (2.5 g, 29 mmol) and pyridine (2.5ml) in CH₂Cl₂ (60 ml) was added isobutyryl chloride (3.1 g, 29 mmol)slowly at 0° C. The resulting mixture was stirred at r.t. for 2 hoursthen washed with H₂O (30 ml×2) and sat. NaCl (25 ml). The combinedorganic phases were dried (Na₂SO₄), concentrated to afford 4.2 g (93%)ester 2(S)-hydroxy-cis-3-butenyl isobutyrate. This ester was dissolvedin THF (10 ml) and was added to a 1.0M LDA soln. (13.5 ml of 2.0M LDAsolution in THF and 13.5 ml of THF) slowly at −78° C. The resultingmixture was allowed to warm up to r.t. and stirred for 2 h and dilutedwith 5% NaOH (40 ml). The organic phase was separated, the aqueous phasewas washed with Et₂O (10 ml). The aqueous solution was collected andacidified with 6N HCl to pH ˜3. The mixture was extracted with ether (30ml×3). The combined ether layers were washed with sat. NaCl (25 ml),dried (Na₂SO₄) and concentrated to afford 2.5 g (60%) of desired acid,m/e=157 (M+H).

PART F: Preparation of benzyl 2,2,3(S)-trimethyl-trans-4-hexenoate

A mixture of acid from Part E (2.5 g, 16 mmol), BnBr (2.7 g, 15.8 mmol),K₂CO₃ (2.2 g, 16 mmol), NaI (2.4 g) in acetone (20 ml) was heated at 75°C. (oil bath) for 16 h. The acetone was stripped off and the residue wasdissolved in H₂O (25 ml) and ether (35 ml). The ether layer wasseparated, dried (Na₂SO₄) and concentrated to afford 3.7 g (95%) ofbenzyl ester, m/e=247 (M+H).

PART G: Preparation of benzyl 2,2,3(R)-trimethylsuccinate

To a well-stirred mixture of KMnO₄ (5.4 g, 34, 2 mmol), H₂O (34 ml),CH₂Cl₂ (6 ml) and benzyltriethylammonium chloride (200 mg) was added asolution of ester from Part F (2.1 g, 8.54 mmol) and acetic acid (6 ml)in CH₂Cl₂ (28 ml) slowly at 0° C. The resulting mixture was stirred atthe temperature for 2 h then r.t. for 16 h. The mixture was cooled in anice-water bath, to this was added 6N HCl (3 ml) and solid NaHSO₃ inportions until the red color disappeared. The clear solution wasextracted with CH₂Cl₂ (30 ml×3). The combined extracts were washed withsat. NaCl solution, dried (Na₂SO₄) and concentrated to give an oil. Thisoil was dissolved in Et₂O (50 ml) and to this was added sat. NaHCO₃ (50ml). The aqueous layer was separated and acidified with 6N HCl to pH ˜3then extracted with Et₂O (30 ml×3). The combined extracts were washedwith sat. NaCl solution (15 ml), dried (Na₂SO₄) and concentrated toafford 725 mg (34%) of desired acid, benzyl 2,2,3(R)-trimethylsuccinate,m/e=251 (M+H).

EXAMPLE 8

Preparation of methyl 2,2-dimethyl-3-methyl succinate, (R) and (S)isomers PART A: Preparation of methyl 2,2-dimethyl-3-oxo-butanoate

A 250 ml RB flask equipped with magnetic stir bar and N₂ inlet wascharged with 100 ml dry THF and 4.57 g (180 mmol) of 95% NaH. The slurrywas cooled to −20° C. and 10 g (87 mmol) methyl acetoacetate was addeddropwise followed by 11.3 ml (181 mmol) CH₃I. The reaction was stirredat 0° C. for 2 hours and let cool to room temperature overnight. Thereaction was filtered to remove NaI and diluted with 125 ml Et₂O. Theorganic phase was washed with 1×100 l 5% brine, dried and concentratedin vacuo to a dark golden oil that was filtered through a 30 g plug ofsilica gel with hexane. Concentration in vacuo yielded 10.05 g ofdesired methyl ester, as a pale yellow oil, suitable for use withoutfurther purification.

PART B: Preparation of methyl2,2-dimethyl-3-0-(trifluoromethanesulfonate)-but-3-enoate

A 250 ml RB flask equipped with magnetic stir bar and N₂ inlet wascharged with 80 mL by THF and 5.25 ml (37.5 mmol) diisopropylamine wasadded. The solution was cooled to −25° C. (dry ice/ethylene glycol) and15 ml (37.5 mmol) of 2.5 M n-BuLi in hexanes was added. After 10 minutesa solution of 5 g (35 mmol) 1 in 8 ml dry THF was added. The deep yellowsolution was stirred at −20° C. for 10 min. then 12.4 g N-phenylbis(trifluoromethane-sulfonimide) (35 mmol) was added. The reaction wasstirred @ −10° C. for 2 hours, concentrated in vacuo and partionedbetween ethyl acetate and sat. NaHCO₃. The combined organic phase waswashed with NaHCO₃, brine and conc. to an amber oil that was filteredthrough a 60 g silica gel plug with 300 mL 5% ethyl acetate/hexane.Conc. in vacuo yielded 9.0 g light yellow oil that was diluted with 65ml ethyl acetate and washed with 2×50 ml 5% aq K₂CO₃, 1×10 mL brine,dried over Na₂SO₄ and conc. in vacuo to yield 7.5 g (87%) vinyltriflate, (m/e=277 (M+H) suitable for use without further purification.

PART C: Preparation of methyl 2,2-dimethyl-3-carboxyl-but-3-enoate

A 250 ml Fisher Porter bottle was charged with 7.5 g (27 mmol) ofcompound prepared in B, 50 ml dry DMF, 360 mg (1.37 mmol) triphenylphosphine and 155 mg (0.69 mmol) Pd(II)(OAc)₂. The reaction mixture waspurged twice with N₂ then charged with 30 psi CO. Meanwhile a solutionof 20 ml dry DMF and 7.56 ml (54 mmol) NEt₃ was cooled to 0° C. to thiswas added 2.0 g (43 mmol) of 99% formic acid. The mixture was swirledand added to the vented Fisher Porter tube. The reaction vessel wasrecharged to 40 psi of CO and stirred 6 hours @ room temperature. Thereaction mixture was concentrated in vacuo and partioned between 100 mLof ethyl acetate and 75 mL 5% aq K₂CO₃. The aqueous phase was washedwith 1×40 mL additional ethyl acetate and then acidified with conc.HCl/ice. The aqueous phase was extracted with 2×70 mL of ethyl acetateand the organics were dried and conc. to yield 3.5 g (75%) whitecrystals, mp 72-75° C., identified as the desired product (m/e=173(M+H).

PART D: Preparation of methyl 2,2-dimethyl-3-methylsuccinate, isomer #1

A steel hydrogenation vessel was charged with 510 mg (3.0 mmol) acrylicacid, from Part C, and 6 mg Ru (acac)₂ (R-BINAP) in 10 ml degassed MeOH.The reaction was hydrogenated at 50 psi/room temperature for 12 hours.The reaction was then filtered through celite and conc. to 500 mg clearoil which was shown to be a 93:7 mixture of isomer #1 and #2,respectively as determined by GC analysis using a 50 M β-cyclodextrincolumn: 150° C. −15 min. then ramp 2° C./min.; isomer #1, 17.85 min.,isomer #2, 18-20 min.

PART E: Preparation of methyl 2,2-dimethyl-3-methylsuccinate, Isomer #2

A steel hydrogenation vessel was charged with 500 mg (2.9 mmol) acrylicacid, Part C, and 6 mg Ru(OAc) (acac)(S-BINAP) in 10 ml degassed MeOH.The reaction was hydrogenated at 50 psi/room temperature for 10 hours.The reaction was filtered through celite and concentrated in vacuo toyield 490 mg of product as a 1:99 mixture of isomers #1 and #2,respectively, as determined by chiral GC as above.

In a similiar manner, one can use benzyl 2,2-dimethyl-3-oxo-butanoate toprepare benzyl 2,2,3-trimethylsuccinate, R and S isomers. Other methodsfor preparing succinic acids, succinates and succinamides are well knownin the art and can be utilized in the present invention.

EXAMPLE 9

Following the procedure generally as set forth in Examples 10 and 11, orutilizing methods well known in the art, the compounds shown in Tables 2and 3 could be prepared. TABLE 2

R¹ R³⁰ R³¹ R³² X′ R³³ R³⁴ H H H H N H H H H H H O H — H H H H O CH₃ —CH₃ H H H N H H CH₃ H H H O H — H H CH₃ H N H H H H CH₃ H O H — CH₃ CH₃H H N H H CH₃ CH₃ H H O H — CH₃ CH₃ H H O CH₂C₆H₄OCH₃ — H H CH₃ CH₃ N HH H H CH₃ CH₃ O H H H CH₃ CH₃ O CH₂C₆H₄OCH₃ — CH₃ H CH₃ H N H H CH₃ HCH₃ H N H CH₃ CH₃ H CH₃ H N CH₃ CH₃ CH₃ H CH₃ H O H — CH₃ H CH₃ H N H—CH₂C₆H₅OCH₃ OH H H H N H H OH H H H O H — H H OH H N H H H H OH H O H —CH₃ H H H N H H CH₃ H H H O H — CH₂C(O)NH₂ H H H N H H CH₂C(O)NH₂ H H HO H — CH₂C(O)NH₂ H H H O CH₃ — CH₂Ph H H H N H H CH₃ H CH₃ CH₃ N H H CH₃H CH₃ CH₃ O H — CH₃ H CH₃ CH₃ N H CH₃ CH₃ H CH₃ CH₃ N CH₃ CH₃

EXAMPLE 10

TABLE 3

EXAMPLE 11

N[3(s)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine(370 mg. 1.0 mmole), prepared as in Example 3, is mixed with DIEA (280μL, 2.0 mmoles) and 1.0 mmole of the sulfamoyl chloride derivative ofmethyl aminoisobutyrate (2 mmol) in a 100 mL round bottomed flaskequipped with a reflux condenser, nitrogen inlet, and magnetic stir bar.The slurry is warmed to reflux and maintained at this temperature forabout 1 hour or is stirred at room temperature for about two days.

A solution of this product (1 mmole) containing 20 mL of methanol and 5mL of acetic acid is hydrogenated over 10% palladium on carbon (80 mg)for 6 h.

The free amine (0.2 mmoles) is then coupled with2,2-dimethyl-3-methylsuccinate (0.3 mmoles) in the presence ofN-hydroxybenzotriazole (0.3 mmoles) and EDC (0.3 mmoles) to yieldproduct.

Utilizing the procedures set forth above, the compounds shown in Tables4-14 could be prepared. Thus, utilizing the intermediates of Examples1-13 according to the procedures in Example 14, the compounds shown inTables 4-16 could be prepared. General methods for preparing suchcompounds are set forth below.

General Procedure for the Synthesis of Amino Epoxide

Part A:

To a solution of 0.226 mol of N-benzyloxycarbonyl-L-amino acidchloromethyl ketone in a mixture of 807 mL of methanol and 807 mL oftetrahydrofuran at −2° C., is added 1.54 equiv. of solid sodiumborohydride over one hundred minutes. The solvents are then removedunder reduced pressure at 40° C. and the residue is dissolved in ethylacetate (approx. 1 L). The solution is washed sequentially with 1Mpotassium hydrogen sulfate, saturated sodium bicarbonate and is thensaturated sodium chloride solutions. After drying over anhydrousmagnesium sulfate and filtering, the solution is removed under reducedpressure. To the resulting oil is added hexane (approx. 1 L) and themixture is warmed to 60° C. with swirling. After cooling to roomtemperature, the solids are collected and washed with 2 L of hexane. Theresulting solid is recrystallized from hot ethyl acetate and hexane toafford 32.3 g (43% yield) ofN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp150-151° C. and M+Li⁺=340.

Part B:

To a solution of 1.2 equiv. of potassium hydroxide in 968 mL of absoluteethanol at room temperature, is added 0.097 mol ofN-CBZ-3(S)-amino-1-chloro-4-substituted-2(S)-butanol. After stirring forfifteen minutes, the solvent is removed under reduced pressure and thesolids are dissolved in methylene chloride. After washing with water,drying over magnesium sulfate, filtering and stripping, one obtains awhite solid. Recrystallization from hot ethyl acetate and hexane willafford N-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane.

Alternate General Procedure for the Synthesis of Amino Epoxides

Step A:

A solution of L-amino acid (0.302 mol), sodium hydroxide (24.2 g, 0.605mol) and potassium carbonate (83.6 g, 0.605 mol) in water (500 ml) isheated to 97° C. Benzyl bromide (108.5 ml, 0.912 mol) is then slowlyadded (addition time ˜25 min). The mixture is then stirred at 97° C. for30 minutes. The solution is cooled to room temperature and extractedwith toluene (2×250 ml). The combined organic layers are then washedwith water, brine, dried over magnesium sulfate, filtered andconcentrated to give an oil product. The crude product is then used inthe next step without purification.

Step B:

The crude benzylated product of the above step is dissolved in toluene(750 ml) and cooled to −55° C. A 1.5 M solution of DIBAL-H in toluene(443.9 ml, 0.666 mol) is then added at a rate to maintain thetemperature between −55° to −50° C. (addition time −1 hour). The mixtureis stirred for 20 minutes at −55° C. The reaction is quenched at −55° C.by the slow addition of methanol (37 ml). The cold solution is thenpoured into cold (5° C.) 1.5 N HCl solution (1.8 L). The precipitatedsolid (approx. 138 g) is filtered off and washed with toluene. The solidmaterial is suspended in a mixture of toluene (400 ml) and water (100ml). The mixture is cooled to 5° C., treated with 2.5 N NaOH (186 ml)and then stirred at room temperature until the solid is dissolved. Thetoluene layer is separated from the aqueous phase and washed with waterand brine, dried over magnesium sulfate, filtered and concentrated to avolume of 75 ml (89 g). Ethyl acetate (25 ml) and hexane (25 ml) arethen added to the residue upon which the alcohol product begins tocrystallize. After 30 min., an additional 50 ml hexane is added topromote further crystallization. The solid is filtered off and washedwith 50 ml hexane to give approximately 35 g of material. A second cropof material can be isolated by refiltering the mother liquor. The solidsare combined and recrystallized from ethyl acetate (20 ml) and hexane(30 ml) to give, in 2 crops, approximately 40 g of analytically purealcohol product. The mother liquors are combined and concentrated (34g). The residue is treated with ethyl acetate and hexane which providesan additional 7 g (˜7% yield) of slightly impure solid product. Furtheroptimization in the recovery from the mother liquor is probable.

Step C:

A solution of oxalyl chloride (8.4 ml, 0.096 mol) in dichloromethane(240 ml) is cooled to −74° C. A solution of DMSO (12.0 ml, 0.155 mol) indichloromethane (50 ml) is then slowly added at a rate to maintain thetemperature at −74° C. (addition time ˜1.25 hr). The mixture is stirredfor 5 min. followed by addition of a solution of the alcohol (0.074 mol)in 100 ml of dichloromethane (addition time −20 min., temp. −75° C. to−68° C.). The solution is stirred at −78° C. for 35 minutes.Triethylamine (41.2 ml, 0.295 mol) is then added over 10 min. (temp.−780 to −68° C.) upon which the ammonium salt precipitated. The coldmixture is stirred for 30 min. and then water (225 ml) is added. Thedichloromethane layer is separated from the aqueous phase and washedwith water, brine, dried over magnesium sulfate, filtered andconcentrated. The residue is diluted with ethyl acetate and hexane andthen filtered to further remove the ammonium salt. The filtrate isconcentrated to give the desired aldehyde product. The aldehyde iscarried on to the next step without purification.

Temperatures higher than −70° C. have been reported in the literaturefor the Swern oxidation. Other Swern modifications and alternatives tothe Swern oxidations are also possible.

A solution of the crude aldehyde 0.074 mol and chloroiodomethane (7.0ml, 0.096 mol) in tetrahydrofuran (285 ml) is cooled to −78° C. A 1.6 Msolution of n-butyllithium in hexane (25 ml, 0.040 mol) is then added ata rate to maintain the temperature at −75° C. (addition time −15 min.).After the first addition, additional chloroiodomethane (1.6 ml, 0.022mol) is added again, followed by n-butyllithium (23 ml, 0.037 mol),keeping the temperature at −75° C. The mixture is stirred for 15 min.Each of the reagents, chloroiodomethane (0.70 ml, 0.010 mol) andn-butyllithium (5 ml, 0.008 mol) are added 4 more times over 45 min. at−75° C. The cooling bath is then removed and the solution warmed to 22°C. over 1.5 hr. The mixture is poured into 300 ml of saturated aq.ammonium chloride solution. The tetrahydrofuran layer is separated. Theaqueous phase is extracted with ethyl acetate (1×300 ml). The combinedorganic layers are washed with brine, dried over magnesium sulfate,filtered and concentrated to give a brown oil (27.4 g). The product canbe used in the next step without purification. The desired diastereomercan be purified by recrystallization at the subsequent sulfonamideformation step.

Alternately, the product can be purified by chromatography.

General Procedure for the Synthesis of 1,3-Diamino 4-phenyl Butan-2-olDerivatives

A mixture of the amine R³NH₂ (20 equiv.) in dry isopropyl alcohol (20mL/mmol of epoxide to be converted) is heated to reflux and then istreated with an N-Cbz amino epoxide of the formula:

from a solids addition funnel over a 10-15 minute period. After theaddition is complete the solution is maintained at reflux for anadditional 15 minutes and the progress of the reaction monitored by TLC.The reaction mixture is then concentrated in vacuo to give an oil and isthen treated with n-hexane with rapid stirring whereupon the ringopened-material precipitates from solution. Precipitation is generallycomplete within 1 hr and the product is then isolated by filtration on aBüchner funnel and is then air dried. The product is further dried invacuo. This method affords amino alcohols of sufficient purity for mostpurposes.General Procedure for the Reaction of Amino Alcohols with SulfamoylHalides: Preparation of Sulfamic Acids

To a solution ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-substituted] N-substitutedamine (0.5 mmol) and a suitable amine (0.5 mmol) in dichloromethane (10mL) is added (0.5 mmol) of the sulfamoyl chloride. The reaction mixtureis stirred until the reaction is substantially complete, such as for 120hours at room temperature, then the dichloromethane solution isconcentrated and applied to a silica gel column (50 gm). The column iseluted with 2% methanol in dichloromethane, 1% ethanol and 1% methanol.

General Procedure for Preparation of Sulfamoyl Chlorides

To a solution of 547 mmol of sulfuryl chloride in 100 mL of anhydrousacetonitrile under a nitrogen atmosphere, was added 136 mmol of aminehydrochloride and the mixture heated to reflux for twenty-four toforty-eight hours. The solution was cooled and concentrated in vacuo toafford a semi-solid. Anhydrous diethyl ether was added, the solidsremoved by filtration are the filtrate concentrated to afford the crudesulfamoyl chloride. This can be used as is, or if desired, purified byeither crystallization or distillation.

General Procedure for the Removal of the Protecting Groups byHydrogenolysis with Palladium on Carbon

A. Alcohol Solvent

The Cbz-protected peptide derivative is dissolved in methanol (ca. 20mL/mmol) and 10% palladium on carbon catalyst is added under a nitrogenatmosphere. The reaction vessel is sealed and flushed 5 times withnitrogen and then 5 times with hydrogen. The pressure is maintained at50 psig for 1-16 hours and then the hydrogen is replaced with nitrogenand the solution is filtered through a pad of celite to remove thecatalyst. The solvent is removed in vacuo to give the free aminoderivative of suitable purity to be taken directly on to the next step.

B. Acetic Acid Solvent

The Cbz-protected peptide derivative is dissolved in glacial acetic acid(20 mL/mmol) and 10% palladium on carbon catalyst is added under anitrogen atmosphere. The reaction vessel is flushed 5 times withnitrogen and 5 times with hydrogen and then maintained at 40 psig forabout 2 h. The hydrogen is then replaced with nitrogen and the reactionmixture filtered through a pad of celite to remove the catalyst. Thefiltrate is concentrated and the resulting product is taken up inanhydrous ether and is evaporated to dryness 3 times. The final product,the acetate salt, is dried in vacuo and is of suitable purity forsubsequent conversion.

General Procedure for Removal of Boc-Protecting Group with 4NHydrochloric Acid in Dioxane

The Boc-protected amino acid or peptide is treated with a solution of 4NHCl in dioxane with stirring at room temperature. Generally thedeprotection reaction is complete within 15 minutes, the progress of thereaction is monitored by thin layer chromatography (TLC). Uponcompletion, the excess dioxane and HCl are removed by evaporation invacuo. The last traces of dioxane and HCl are best removed byevaporation again from anhydrous ether or acetone. The hydrochloridesalt thus obtained is thoroughly dried in vacuo and is suitable forfurther reaction. TABLE 4

Entry X R³ R¹⁶ 1 NH₂ CH₃ H 2 NH₂ i-Butyl CH₃ 3 NH₂ i-Butyl CH₂CH₃ 4 OHi-Butyl CH(CH₃)₂ 5 NH₂ i-Propyl C(CH₃)₃ 6 OH i-Propyl CH₂Ph 7 NH₂ C₆H₅ H8 NH₂

CH₃ 9 NH₂

C(CH₃)₃ 10 OH

H 11 NH₂

CH₂CH₃ 12 NH₂ i-Butyl C(CH₃)₃ 13 OH i-Butyl H 14 OH

CH₃ 15 OH

CH₂CH₃ 16 OH

CH(CH₃)₂ 17 OH i-Butyl C(CH₃)₃ 18 OH i-Butyl CH₂Ph 19 NH₂ i-Butyl H 20NH₂ i-Butyl CH₃ 21 OH

C(CH₃)₃ 22 OH (CH₂)₂CH(CH₃)₂ H 23 NH₂ i-Butyl CH₂CH₃ 24 OH i-ButylC(CH₃)₃ 25 NH₂ i-Butyl H 26 OH

CH₃ 27 NH₂

CH₂CH₃ 28 OH —(CH₂)₂CH(CH₃)₂ CH(CH₃)₂ 29 NH₂ —(CH₂)₂CH(CH₃)₂ C(CH₃)₃ 30OH —CH₂C6H₅ CH₂Ph 31 NH₂ —CH₂C₆H₅ H 32 OH —(CH₂)₂C₆H₅ CH₃ 33 NH₂—(CH₂)₂C₆H₅ C(CH₃)₃ 34 OH n-Butyl H 35 OH n-Pentyl CH₂CH₃ 36 OH n-HexylC(CH₃)₃ 37 OH

H 38 OH —CH₂C(CH₃)₃ CH₂CH₂CH₂CH₃ 39 NH₂ —CH₂C(CH₃)₃ CH₂CH₂CH₂CH₃ 40 OH

CH(CH₃)₂ 41 OH —CH₂C₆H₅OCH₃(para) C(CH₃)₃ 42 OH

CH₂Ph 43 OH

H 44 OH —(CH₂)₂C(CH₃)₃ CH₃ 45 NH₂ —(CH₂)₂C(CH₃)₃ C(CH₃)₃ 46 OH —(CH₂)₄OHH 47 NH₂ —(CH₂)₄OH CH₂CH₃ 48 NH₂

C(CH₃)₃ 49 NH₂

H 50 OCH₂Ph —CH₂CH(CH₃)₂ CH₃ 51 OCH₂Ph —CH₂CH(CH₃)₂ CH₂CH₃ 52 NH₂—CH₂CH(CH₃)₂ CH(CH₃)₂ 53 OCH₂Ph —CH₂CH(CH₃)₂ C(CH₃)₃ 54 OH —CH₂CH(CH₃)₂CH₂Ph 55 NH₂ —CH₂CH(CH₃)₂ H 56 OCH₂Ph —CH₂CH(CH₃)₂ CH₃ 57 OH—CH₂CH(CH₃)₂ C(CH₃)₃ 58 NH₂ —CH₂CH(CH₃)₂ H 59 OCH₂Ph —CH₂CH(CH₃)₂ CH₂CH₃60 OH —CH₂CH(CH₃)₂ C(CH₃)₃ 61 NH₂ —CH₂CH(CH₃)₂ H 62 OCH₂Ph —CH₂CH(CH₃)₂CH₃ 63 OH —CH₂CH(CH₃)₂ CH₂CH₃ 64 NH₂ —CH₂CH(CH₃)₂ CH(CH₃)₂ 65 OCH₂Ph—CH₂CH(CH₃)₂ C(CH₃)₃ 66 OH —CH₂CH(CH₃)₂ CH₂Ph 67 NH₂ —CH₂CH(CH₃)₂ H 68OCH2Ph —CH₂CH(CH₃)₂ CH₃ 69 OH —CH₂CH(CH₃)₂ C(CH₃)₃ 70 NH₂ —CH₂Ph H 71OCH₂Ph

CH₂CH₃ 72 OH

C(CH₃)₃ 73 NH₂

H 74 OCH₂Ph

CH₃ 75 OH

H 76 NH₂ —CH₂CH═CH₂ CH₃ 77 OCH₂Ph

CH₂CH₃ 78 OH

CH(CH₃)₂ 79 NH₂ —CH₂CH₂Ph C(CH₃)₃ 80 OCH₂Ph —CH₂CH₂CH₂CH₂OH CH₂Ph 81 OH—CH₂CH₂N(CH₃)₂ H 82 NH₂

CH₃ 83 OCH₂Ph —CH₃ C(CH₃)₃ 84 OH —CH₂CH₂CH₂SCH₃ H 85 NH₂—CH₂CH₂CH₂S(O)₂CH₃ CH₂CH₃

TABLE 5

Entry R¹ 1 CH₂SO₂CH₃ 2 (R)—CH(OH)CH₃ 3 CH(CH₃)₂ 4 (R,S)CH₂SOCH₃ 5CH₂SO₂NH₂ 6 CH₂SCH₃ 7 CH₂CH(CH₃)₂ 8 CH₂CH₂C(O)NH₂ 9 (S)—CH(OH)CH₃ 10—CH₂C≡CH 11 —CH₂CH₃ 12 —CH₂C(O)NH₂ 13 —C(CH₃)₂SO₂CH₃ 14 —CH₂CH═CH₂ 15—C(CH₃)₂SCH₃

TABLE 6

Entry R² 1 n-Bu 2 cyclohexylmethyl 3 C₆H₅CH₂ 4 2-naphthylmethyl 5p-F(C₆H₄)CH₂ 6 p-(PhCH₂O)(C₆H₄)CH₂ 7 p-HO(C₆H₄)CH₂ 8 (CH₂)₂SCH₃

TABLE 7

Entry R³ R¹⁶ 1 —CH₂CH(CH₃)₂ —CH(CH₃)₂ 2 —CH₂CH(CH₃)₂

3 —CH₂CH(CH₃)₂

4 —CH₂CH(CH₃)₂

5 —CH₂CH(CH₃)₂

TABLE 8

Entry R¹ R³⁰ R³¹ R³² X′ R³³ R³⁴ 1 H H H H N H H 2 H H H H O H — 3 H H HH O CH₃ — 4 CH₃ H H H N H H 5 CH₃ H H H O H — 6 H H CH₃ H N H H 7 H HCH₃ H O H — 8 CH₃ CH₃ H H N H H 9 CH₃ CH₃ H H O H — 10 CH₃ CH₃ H H OCH₂C₆H₄OCH₃ — 11 H H CH₃ CH₃ N H H 12 H H CH₃ CH₃ O H 13 H H CH₃ CH₃ OCH₂C₆H₄OCH₃ — 14 CH₃ H CH₃ H N H H 15 CH₃ H CH₃ H N H CH₃ 16 CH₃ H CH₃ HN CH₃ CH₃ 17 CH₃ H CH₃ H O H — 18 CH₃ H CH₃ H O —CH₂C₆H₅OCH₃ — 19 OH H HH N H H 20 OH H H H O H — 21 H H OH H N H H 22 H H OH H O H — 23 CH₂ H HH N H H 24 CH₂C(O)NH₂ H H H N H H 25 CH₂C(O)NH₂ H H H O H — 26CH₂C(O)NH₂ H H H O CH₃ — 27 CH₂Ph H H H N H H 28 CH₃ H CH₃ CH₃ O CH₂Ph —29 CH₃ H CH₃ CH₃ O H — 30 CH₃ H CH₃ CH₃ N H H 31 CH₃ H CH₃ CH₃ N H CH₃32 CH₃ H CH₃ CH₃ N CH₃ CH₃ 33 CH₂CH₃ H CH₃ CH₃ O H — 34 CH₂CH₃ H CH₃ CH₃N H H 35 CH₃ H CH₂CH₃ CH₂CH₃ O H — 36 CH₃ H CH₂CH₃ CH₂CH₃ N H H

TABLE 9

TABLE 10

R³ R¹⁶ —CH₂CH(CH₃)₂ —N(CH₃)₂ —CH₂CH(CH₃)₂ —N(CH₂CH₃)₂ —CH₂CH(CH₃)₂—N(CH(CH₃)₂)₂ —CH₂CH₂CH(CH₃)₂ —N(CH₃)₂ —CH₂CH₂CH(CH₃)₂ —N(CH₂CH₃)₂—CH₂CH₂CH(CH₃)₂

—N(CH₃)₂ —N(CH₂CH₃)₂

N(CH₃) (t-Bu)

—CH₂CH(CH₃)₂

—CH₂CH(CH₃)₂

TABLE 11

R³ R¹⁶ —CH₂CH(CH₃)₂ —N(CH₃)₂ —CH₂CH(CH₃)₂ —N(CH₂CH₃)₂ —CH₂CH(CH₃)₂—N(CH(CH₃)₂)₂ —CH₂CH₂CH(CH₃)₂ —N(CH₃)₂ —CH₂CH₂CH(CH₃)₂ —N(CH₂CH₃)₂—CH₂CH₂CH(CH₃)₂

—N(CH₃)₂ —N(CH₂CH₃)₂

N(CH₃) (t-Bu)

—CH₂CH(CH₃)₂

—CH₂CH(CH₃)₂

TABLE 12

n R³ R⁸ 0 —CH₂CH(CH₃)₂ —CN 0 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂ —C(O)N(CH₃)₂ 1 —CH₂CH₂CH(CH₃)₂ —CO₂CH₃ 2—CH₂CH₂CH(CH₃)₂

1

1

O —CH₂CH₂CH(CH₃)₂

O

1

1 —CH₂CH(CH₃)₂ OH 1

OH 2

2

1

—SCH₃ 1

—SO₂CH₃ 1

—SO₂CH₃ 1 —CH₂CH(CH₃)₂ —CO₂CH₃ 1

—CO₂H 1

1

—SO₂Ph 1

—SO₂Ph 1 —CH₂CH₂CH(CH₃)₂

2 —CH₂CH₂CH(CH₃)₂ —N(CH₃)₂ 2 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂ —N(CH₃)Ph 1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

EXAMPLE 13

The compounds of the present invention are effective HIV proteaseinhibitors. Utilizing an enzyme assay as described below, the compoundsset forth in the examples herein would be expected to inhibit the HIVenzyme. The enzyme method is described below. The substrate is2-Ile-Nle-Phe(p-NO₂)-Gln-ArgNH₂. The positive control is MVT-101(Miller, M. et al, Science, 246, 1149 (1989)] The assay conditions areas follows:

Assay Buffer:

-   -   20 mM sodium phosphate, pH 6.4    -   20% glycerol    -   1 mM EDTA    -   1 mM DTT    -   0.1% CHAPS

The above described substrate is dissolved in DMSO, then diluted 10 foldin assay buffer. Final substrate concentration in the assay is 80 μM.

HIV protease is diluted in the assay buffer to a final enzymeconcentration of 12.3 nanomolar, based on a molecular weight of 10,780.

The final concentration of DMSO is 14% and the final concentration ofglycerol is 18%. The test compound is dissolved in DMSO and diluted inDMSO to 10× the test concentration; 10 μl of the enzyme preparation isadded, the materials mixed and then the mixture is incubated at ambienttemperature for 15 minutes. The enzyme reaction is initiated by theaddition of 40 μl of substrate. The increase in fluorescence ismonitored at 4 time points (0, 8, 16 and 24 minutes) at ambienttemperature. Each assay is carried out in duplicate wells.

EXAMPLE 14

The effectiveness of the compounds can also be determined in a CEM cellassay.

The HIV inhibition assay method of acutely infected cells is anautomated tetrazolium based calorimetric assay essentially that reportedby Pauwles et al, J. Virol. Methods, 20, 309-321 (1988). Assays can beperformed in 96-well tissue culture plates. CEM cells, a CD4⁺ cell line,were grown in RPMI-1640 medium (Gibco) supplemented with a 10% fetalcalf serum and were then treated with polybrene (2 μg/ml). An 80 μlvolume of medium containing 1×10⁴ cells is dispensed into each well ofthe tissue culture plate. To each well is added a 100 μl volume of testcompound dissolved in tissue culture medium (or medium without testcompound as a control) to achieve the desired final concentration andthe cells are incubated at 37° C. for 1 hour. A frozen culture of HIV-1is diluted in culture medium to a concentration of 5×10⁴ TCID₅₀ per ml(TCID₅₀=the dose of virus that infects 50% of cells in tissue culture),and a 20 μL volume of the virus sample (containing 1000 TCID₅₀ of virus)is added to wells containing test compound and to wells containing onlymedium (infected control cells). Several wells receive culture mediumwithout virus (uninfected control cells). Likewise, the intrinsictoxicity of the test compound is determined by adding-medium withoutvirus to several wells containing test compound. In summary, the tissueculture plates contain the following experiments: Cells Drug Virus 1. +− − 2. + + − 3. + − + 4. + + +

In experiments 2 and 4 the final concentrations of test compounds are 1,10, 100 and 500 μg/ml. Either azidothvmidine (AZT) or dideoxyinosine(ddI) is included as a positive drug control. Test compounds aredissolved in DMSO and diluted into tissue culture medium so that thefinal DMSO concentration does not exceed 1.5% in any case. DMSO is addedto all control wells at an appropriate concentration.

Following the addition of virus, cells are incubated at 37° C. in ahumidified, 5% CO₂ atmosphere for 7 days. Test compounds could be addedon days 0, 2 and 5 if desired. On day 7, post-infection, the cells ineach well are resuspended and a 100 μl sample of each cell suspension isremoved for assay. A 20 μL volume of a 5 mg/ml solution of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) isadded to each 100 μL cell suspension, and the cells are incubated for 4hours at 27° C. in a 5% CO₂ environment. During this incubation, MTT ismetabolically reduced by living cells resulting in the production in thecell of a colored formazan product. To each sample is added 100 μl of10% sodium dodecylsulfate in 0.01 N HCl to lyse the cells, and samplesare incubated overnight. The absorbance at 590 nm is determined for eachsample using a Molecular Devices microplate reader. Absorbance valuesfor each set of wells is compared to assess viral control infection,uninfected control cell response as well as test compound bycytotoxicity and antiviral efficacy.

The compounds of the present invention are effective antiviral compoundsand, in particular, are effective retroviral inhibitors as shown above.Thus, the subject compounds are effective HIV protease inhibitors. It iscontemplated that the subject compounds will also inhibit otherretroviruses such as other lentiviruses in particular other strains ofHIV, e.g. HIV-2, human T-cell leukemia virus, respiratory syncitialvirus, simia immunodeficiency virus, feline leukemia virus, felineimmuno-deficiency virus, hepadnavirus, cytomegalovirus and picornavirus.Thus, the subject compounds are effective in the treatment and/orproplylaxis of retroviral infections.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or nonracemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, for example byformation of diastereoisomeric salts by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of Formula Iwith an optically pure acid in an activated form or an optically pureisocyanate. The synthesized diastereoisomers can be separated byconventional means such as chromatography, distillation, crystallizationor sublimation, and then hydrolyzed to deliver the enantiomerically purecompound. The optically active compounds of Formula I can likewise beobtained by utilizing optically active starting materials. These isomersmay be in the form of a free acid, a free base, an ester or a salt.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Total daily dose administered to a host in single or divided doses maybe in amounts, for example, from 0.001 to 10 mg/kg body weight daily andmore usually 0.01 to 1 mg. Dosage unit compositions may contain suchamounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized andwhether the compound is administered as part of a drug combination.Thus, the dosage regimen actually employed may vary widely and thereforemay deviate from the preferred dosage regimen set forth above.

The compounds of the present invention may be administered orally,parenterally, by inhalation spray, rectally, or topically in dosage unitformulations containing conventional nontoxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles as desired. Topicaladministration may also involve the use of transdermal administrationsuch as transdermal patches or iontophoresis devices. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more immunomodulators, antiviral agents or other antiinfectiveagents. For example, the compounds of the invention can be administeredin combination with AZT, DDI, DDC or with glucosidase inhibitors, suchas N-butyl-1-deoxynojirimycin or prodrugs thereof, for the prophylaxisand/or treatment of AIDS. When administered as a combination, thetherapeutic agents can be formulated as separate compositions which aregiven at the same time or different times, or the therapeutic agents canbe given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1-26. (canceled)
 27. A compound represented by the formula:

or a pharmaceutically acceptable salt thereof, wherein: R¹ represents aradical selected from the group consisting of hydrogen, —CH₂SO₂NH₂,—CH₂CO₂CH₃, —CO₂CH₃, —CONH₂, —CH₂CONHCH₃, —C(CH₃)₂SH, —C(CH₃)₂SCH₃,—C(CH₃)₂(SOCH₃), —C(CH₃)₂(SO₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl,cycloalkyl, a side chain of an amino acid selected from the groupconsisting of asparagine, isoleucine, allo-isoleucine, alanine, leucine,tert-leucine, phenylalanine, ornithine, histidine, norleucine,glutamine, threonine, glycine, allo-threonine, serine, O-alkyl serine,aspartic acid, beta-cyano alanine, valine, S-methyl cysteine,methionine, and the sulfoxide (SO) and sulfone (SO₂) derivatives ofS-methyl cysteine and methionine; R² represents a radical selected fromthe group consisting of alkyl; aryl; cycloalkyl; cycloalkylalkyl;aralkyl; and alkyl, aryl, cycloalkyl, cycloalkylalkyl, or aralykyl thatis substituted with a radical selected from the group consisting ofalkyl, halogen, —NO₂, —CN, —CF₃, —OR⁹, —SR⁹, wherein R⁹ is a hydrogen oran alkyl radical; R³ represents a radical selected from the groupconsisting of alkyl; haloalkyl; alkenyl; alkynyl; hydroxyalkyl;alkoxyalkyl; cycloalkyl; cycloalkylalkyl; heterocycloalkyl; heteroaryl;heterocycloalkylalkyl; aryl; aralkyl; heteroaralkyl; aminoalkyl;aminoalkyl substituted at one or more carbon atoms with a radicalselected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, andheterocycloalkylalkyl; aminoalkyl substituted at two carbon atoms withradicals that, together with the nitrogen atom to which they areattached, form a heterocycloalkyl or a heteroaryl radical; thioalkyl;alkylthioalkyl; arylthioalkyl; and the sulfone and sulfoxide derivativesof thioalkyl, alkylthioalkyl, and arylthioalkyl; R⁴ is a hydrogenradical or a radical as defined for R³; R⁶ is a hydrogen radical or analkyl radical; R⁷ and R^(7′) independently represent a radical selectedfrom the group consisting of hydrogen; a radical as defined for R³; anamino acid side chain selected from the group consisting of valine,isoleucine, glycine, alanine, allo-isoleucine, asparagine, leucine,glutamine, and t-butylglycine; —COR¹⁶; —CO₂R¹⁶; —SO₂R¹⁶; —SR¹⁶;—CONR¹⁶R⁷; —CF₃; and —NR¹⁶R¹⁷; or R⁷ and R^(7′), together with thecarbon atom to which they are attached, form a cycloalkyl orheterocycloalkyl radical; R⁸ represents a radical selected from thegroup consisting of cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl,aralkyl, heterocycloalkyl, heteroaryl, —COR¹⁶; —CO₂R¹⁶; —SO₂R¹⁶; —SR¹⁶;—CONR¹⁶R¹⁷; —CF₃; and —NR¹⁶R¹⁷; R¹⁶ and R¹⁷ independently represent ahydrogen radical or a radical defined for R³, or R¹⁶ and R¹⁷, togetherwith the nitrogen to which they are attached in the formula NR¹⁶R¹⁷,represent heterocycloalkyl and heteroaryl radicals; R³⁰, R³¹, and R³²independently represent a radical as defined for R¹, or one of R¹ andR³⁰, together with one of R³¹ and R³² and the carbon atoms to which theyare attached, form a cycloalkyl radical; R³³ and R³⁴ independentlyrepresent a hydrogen radical or a radical as defined for R³, or R³³ andR³⁴, together with X′, represent a radical selected from the groupconsisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl, providedthat when X′ is O, R³⁴ is absent; X′ represents N, O, or CR¹⁷, whereinR¹⁷ is a hydrogen radical or an alkyl radical; x is 1 or 2; n is aninteger from 0 to 6; t is 0, 1, or 2; and Y and Y′ independentlyrepresent O, S or NR¹⁵, wherein R¹⁵ is a hydrogen radical or a radicalas defined for R³.
 28. A pharmaceutical composition comprising acompound of claim 27 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.
 29. A method of inhibiting aretroviral protease comprising administering a protease inhibitingamount of a composition of claim
 28. 30. The method of claim 29, whereinsaid retroviral protease is HIV protease.
 31. A method of treating aretroviral infection comprising administering an effective amount of acomposition of claim
 28. 32. The method of claim 31 wherein saidretroviral infection is an HIV infection.
 33. A method for treating AIDScomprising administering an effective amount of a composition of claim28.
 34. A compound represented by the formula:

or a pharmaceutically acceptable salt thereof, wherein: R¹ represents aradical selected from the group consisting of hydrogen, —CH₂SO₂NH₂,—CH₂CO₂CH₃, —CO₂CH₃, —CONH₂, —CH₂CONHCH₃, —C(CH₃)₂SH, —C(CH₃)₂SCH₃,—C(CH₃)₂(SOCH₃), —C(CH₃)₂(SO₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl,cycloalkyl, a side chain of an amino acid selected from the groupconsisting of asparagine, isoleucine, allo-isoleucine, alanine, leucine,tert-leucine, phenylalanine, ornithine, histidine, norleucine,glutamine, threonine, glycine, allo-threonine, serine, aspartic acid,beta-cyano alanine, valine, S-methyl cysteine, methionine, and thesulfoxide (SO) and sulfone (SO₂) derivatives of S-methyl cysteine andmethionine; R² represents a radical selected from the group consistingof alkyl; aryl; cycloalkyl; cycloalkylalkyl; aralkyl; and alkyl, aryl,cycloalkyl, cycloalkylalkyl, or aralykyl that is substituted with aradical selected from the group consisting of alkyl, halogen, —NO₂, —CN,—CF₃, —OR⁹, —SR⁹, wherein R⁹ is a hydrogen or an alkyl radical; R³represents a radical selected from the group consisting of alkyl;haloalkyl; thioalkyl; alkenyl; alkynyl; hydroxyalkyl; alkoxyalkyl;alkylthioalkyl; cycloalkyl; cycloalkylalkyl; heterocycloalkyl;heteroaryl; heterocycloalkylalkyl; aryl; aralkyl; heteroaralkyl;aminoalkyl; aminoalkyl substituted at one or more carbon atoms with aradical selected from the group consisting of alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, and heterocycloalkylalkyl; aminoalkyl substituted attwo carbon atoms with radicals that, together with the nitrogen atom towhich they are attached, form a heterocycloalkyl or a heteroarylradical; R⁴ is a hydrogen radical or a radical as defined for R³; R⁷ andR^(7′) independently represent a radical as defined for R³; an aminoacid side chain selected from the group consisting of valine,isoleucine, glycine, alanine, allo-isoleucine, asparagine, leucine,glutamine, and t-butylglycine; or R⁷ and R^(7′), together with thecarbon atom to which they are attached, form a cycloalkyl radical; R⁸represents a radical selected from the group consisting of cyano,hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, aralkyl, heterocycloalkyl,heteroaryl, —COR¹⁶; —CO₂R¹⁶; —SO₂R¹⁶; —SR¹⁶; —CONR¹⁶R¹⁷; —CF₃; and—NR¹⁶R¹⁷; R¹⁶ and R¹⁷ independently represent a hydrogen radical or aradical defined for R³, or R¹⁶ and R¹⁷, together with the nitrogen towhich they are attached in the formula NR¹⁶R¹⁷, representheterocycloalkyl and heteroaryl radicals; R³⁰, R³¹, and R³²independently represent a radical as defined for R¹, or one of R¹ andR³⁰, together with one of R³¹ and R³² and the carbon atoms to which theyare attached, form a cycloalkyl radical; R³³ represents a hydrogenradical or a radical as defined for R³; and n represents an integer offrom 0 to
 6. 35. The compound of claim 34 or a pharmaceuticallyacceptable salt thereof, wherein R¹ represents a radical selected fromthe group consisting of hydrogen, alkyl, alkenyl, a side chain of anamino acid selected from the group consisting of asparagine, valine,threonine, allo-threonine, isoleucine, tert-leucine, S-methyl cysteine,methionine, and the sulfoxide (SO) and sulfone (SO₂) derivatives ofS-methyl cysteine and methionine; R² represents a radical selected fromthe group consisting of alkyl; cycloalkyl; and aralkyl; and alkyl,cycloalkyl, or aralykyl that is substituted with a halogen radical or—OR⁹, wherein R⁹ is a hydrogen or an alkyl radical; R³ represents aradical selected from the group consisting of alkyl, haloalkyl,thioalkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl,heteroaryl, and heteroaralkyl; R⁴ represents a radical selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,heteroaryl, aralykyl, heteroaralkyl, heterocycloalkyl, andheterocycloalkylalkyl; R³⁰, R³¹, and R³² independently represent aradical selected from the group consisting of hydrogen, alkyl, alkenyl,and alkynyl, or one of R¹ and R³⁰, together with one of R³¹ and R³² andthe carbon atoms to which they are attached, form a cycloalkyl radical;R³³ represents a radical selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, andheteroaralkyl; and n represents an integer of from 0 to
 4. 36. Thecompound of claim 35 or a pharmaceutically acceptable salt thereof,wherein R¹ represents a radical selected from the group consisting ofhydrogen, methyl, propargyl, t-butyl, isopropyl, sec-butyl, and a sidechain of an amino acid selected from the group consisting of asparagine,valine, S-methyl cysteine, allo-isoleucine, threonine, serine, asparticacid, beta-cyano alanine, and allo-threonine; R² represents a radicalselected from the group consisting of —CH₂CH₂SCH₃, isobutyl, n-butyl,benzyl, 4-fluorobenzyl, 2-naphthylmethyl, and cyclohexylmethyl; R³represents a radical selected from the group consisting of propyl,isobutyl, isoamyl, n-butyl, cyclohexylmethyl, benzyl, and pyridylmethyl;R⁴ represents a radical selected from the group consisting of hydrogen,methyl, ethyl, i-propyl, propyl, n-butyl, t-butyl, cyclohexyl,1,1-dimethylpropyl, and phenyl; R⁷ and R^(7′) independently representmethyl, ethyl, propyl, and butyl, or R⁷ and R⁷, together with the carbonatom to which they are attached, form cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl; R⁸ represents methylcarbonyl, phenyl,hydroxy, methoxy, cyano, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, carboxyl,methoxycarbonyl, methylsulfonyl, methylthio, phenylsulfonyl, phenyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl N-oxide, 3-pyridyl N-oxide,4-pyridyl N-oxide, N,N-dimethylamino, 1-piperidinyl, 4-morpholinyl,4-(N-methyl)piperazinyl, and 1-pyrrolidinyl; R³⁰, R³¹, and R³²independently represent a radical selected from the group consisting ofhydrogen, methyl, ethyl, propyl, butyl, pentyl, and hexyl, or one of R¹and R³⁰, together with one of R³¹ and R³² and the carbon atoms to whichthey are attached, form a cycloalkyl radical having from 3 to 8 carbonatoms; R³³ represents a radical selected from the group consisting ofhydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, teriarybutyl, pentyl, hexyl, cyclohexyl, benzyl, and naphthylmethyl; and, nrepresents an integer of from 0 to
 6. 37. A pharmaceutical compositioncomprising a compound of claim 34 or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier.
 38. A method ofinhibiting a retroviral protease comprising administering a proteaseinhibiting amount of a composition of claim
 38. 39. The method of claim38, wherein said retroviral protease is HIV protease.
 40. A method oftreating a retroviral infection comprising administering an effectiveamount of a composition of claim
 37. 41. The method of claim 40 whereinsaid retroviral infection is an HIV infection.
 42. A method for treatingAIDS comprising administering an effective amount of a composition ofclaim 37.